Effects of Cymbalta on the Body
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Hypothyroidism. It is a common side effect of the use of ssri/snri antidepressants. The medicine inserts that come with antidepressants nearly always warn of the risk of developing hypothyroidism and/or liver damage. These chemicals (medicines) are often suppressive to the function of these tissues. It is standard procedure that a psychiatrist will stop the use of ssri/snri for 3 months to allow the thyroid to recover (which it almost always does unless actual damage is done to the tissue). At that point a different ssri/snri will be used to see if it can be used without effect on the thyroid. Zoloft is the one with the best record. It is important to note that it is essential to consider any radiological testing that may have been done around the same time. It has been shown that around 30% of the abdominal cat scans use enough contrast iodine to produce hypothyroidism. It is usually asymptomatic and does return to normal within a 6 to 9 month period. A simple 24 hour urine sample can show if iodine toxicity (from cat scans/radiation imaging) is the source of the hypothyroidism.
FH - NO good endocrinologist would put you on thyroid medicine immediately after blood tests suggesting hypothyroidism unless you are very symptomatic and in despite need for help. I was diagnosed with HypoT after being on Cymbalta. My primary care dr said I would have to be on thyroid medicine for life. I went to my endocrinologist and he threw a fit. I was informed, but was already aware, that many conditions can causes hypoT blood test results including the radiation, aspirin usage and some of the other nsaids, many other medicines, as well as infections. All clear when the causative agent is removed. Even a seafood diet and/or heavy iodine salt usage can cause this.
http://www.cymbaltaw...tion/?hl=helped
List of AD that can cause thyroid issues.
http://www.cymbaltaw...rove#entry46513
Hypothyroidism and depression information.
Antidepressants
reboxetine - TSH reduced and T4 increased.
sertraline - TSH increased and T4 reduced.
https://www.ncbi.nlm.../?term=18262705
sertraline and fluoxetine showed reductions in TSH,T3 and T4 levels.
https://www.ncbi.nlm.../?term=15486607
Fluoxetine decreased T3 and T4, increased TSH
https://www.ncbi.nlm...d/?term=6413229
Do not treat with thyroid hormones if hypothyroidism is asymptomatic.
These are often accompanied by findings such as low blood pressure, low blood glucose (N), low sodium (N), high potassium (N), and high calcium(N).
https://www.ncbi.nlm...pubmed/22450350
Escitalopram-induced subclinical hypothyroidism. A case report.
https://www.ncbi.nlm...pubmed/20851281
Reversible escitalopram-induced hypothyroidism.
https://www.ncbi.nlm...pubmed/17874352
Reversible paroxetine-induced symptomatic hypothyroidism.
https://www.ncbi.nlm...pubmed/11054982
Depressed patients should be screened for hypothyroidism. In hypothyroid patients, depression may be more responsive to a replacement regimen that includes T3 rather than T4 alone. Therefore, inclusion of T3 in the treatment regimen may be warranted after adequate trial with T4 alone.
https://www.ncbi.nlm.../pubmed/7779834
Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent.
And many more articles.
ssri/snri replacement is a viable option.
https://www.drugs.com/pro/effexor.html
Side effects
"Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis."
https://dailymed.nlm...54-00144ff88e88
The same is mentioned in the section on 'adverse reactions' in the drug insert for Effexor.
http://www.ehealthme...hypothyroidism/
65,121 people reported to have side effects when taking Effexor.
Among them, 420 people (0.64%) have Hypothyroidism
http://www.ehealthme...hypothyroidism/
An FDA supported website.
84,701 people reported to have side effects when taking Cymbalta.
Among them, 292 people (0.34%) have Hypothyroidism
https://dailymed.nlm...f2-c185fbad64ba
Drug insert. (Cymbalta)
Endocrine Disorders — Infrequent: hypothyroidism.
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Tinnitus
Partial list of entries on this site referring to tinnitus.
You will see a pattern, the faster the withdrawal the worse the tinnitus and the longer lasting the occurrence. It also seems to be more common in those on the generic form.
Medical journal info to follow.
Bee 11/29/11
I have been on Cymbalta for 6+ years, also taking 60mg 2x day. I have constant tinnitus.
Marcia 1/24/12
On my journey I am a few days off cymbalta and have the brain zaps, inc tinnitus, aches and pains, chills.
Marcia 1/26/12
Not 10 minutes go by without brain zaps of varying degrees as well as severe tinnitus. At times its just the usual ocean sound, but at times it is a whooshing, pulsating pressure feeling/sound that is very disconcerting.
Jenni 1/26/12 (during withdrawal)
My osteopath found that my neck was very seized up which doesn't help with neck/head/sinus/ear pain and tinnitus. All my symptoms felt better after my appt including the whooshing noise. Maybe a back massage or even just lying in a hot, shallow bath.
BuzzBuzz 3/23/13 (during withdrawal)
The brain zaps and tinnitus are pretty bad,...
SusanMoore 3/28/13 (during withdrawal)
I have also developed what I now know as Tinnitus and this I am told, does not go away.
Answer from lady Nancy
Don't worry Susan the Tinnitus does go away, it takes awhile but it will go away
THP 3/30/13 (during withdrawal)
I started at 60 mg per day and tried to go to every other day which was a nightmare. Severe tinnitus, nausea, emotions, etc.
Lady Nancy 4/16/13 and many many other times. An excert from section 5.7 of the drug insert for Cymbalta.
"During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been
spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including
the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.
Although these events are generally self-limiting, some have been reported to be severe."
Fishinghat 4/17/13 Posted full excert.
5.7 Discontinuation of Treatment with Cymbalta
Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.
Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose maybe considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4)].
Zappinist 5/19/13 during withdrawal
No tinnitus right now, which has been bad recently, but zaps are still there.
Tomitsu 6/11/13 dw
I do have tinnitus and I get the odd brain zap here and there.
Dogs Rule 7/2/13 7 weeks off
This withdrawal will not stop. The really hideous days of zaps and sweating and nausea are over, but lingering symptoms remain: dizziness, tinnitus, and milder zaps.
Irish Eyes 3/21/13
I quit taking Cymbalta in June 2012. I had brain zaps, impaired mental processing, the swishing sound when you move your eyes side to side and tinnitus.
By the end of August I felt almost normal. Then my left foot started tingling. Then in October I got tinnitus.
Last week I start having the swishing sound when I move my eyes back and forth but just when I first wake up.
It's been 9 months and I'm having some of the same symptoms I had in July. Anybody else out there experiencing this?
Afg1202 10/4/13
And this tuning-fork-in-my-head feeling is horrible. And there is so little literature on what helps tinnitus
Thismoment 1/5/14
I might describe my own withdrawal experience like this- bead counting from 30 mg over 6 weeks @ 2.3%.
Difficult// weeks 1-2 smooth/ weeks 3-6 coarse/ weeks 7-12 medium/ weeks 13-24 fine + some medium/ weeks 25-48 fine/ weeks 49-52 smooth/ weeks 53-68 smooth and still improving subtly. I still have two symptoms that are probably permanent- a continuous tension-type headache and tinnitus in my right ear.
Thismoment 1/7/14
My last Cymbalta bead was the end of July 2012, which is getting close to a year and a half now. I still have two symptoms I didn't have before I started the drug. I have a constant headache, and tinnitus in my right ear. Both are tolerable, and I consider myself lucky because after 2 years on the drug I was fried...
FiveNotions 2/18/14
I've had severe tinnitus thanks to cymbalta....it had been so bad that I cldnt hear people talking directly to me...now it's faded a bit, and I have periods of time where it's almost gone...last week I was able to hear my kitchen clock tick! Today, it's bad, like a jet engine in my head...I've had it so long, years, that I've trained myself not to notice it....
Clara 2/26/14
I wish I had a cure for this constant tinnitus. It drives me nuts at times. Just another Cymbalta gift that refuses to go away!
BelaLugosisDad 3/5/14
Tinnitus. - non stop in both ears.
ThisMoment 3/14/14
I've been off Cymbalta for nearly 20 months, and I think I'm probably 95% back; I'm still a little achy in my muscles, I have tinnitus in my right ear, and I have a constant (24/7) tension-type headache that no NSAID will touch. These items are probably chronic, but I'll report back when I hit the 2 year mark this summer.
ThisMoment 3/23/14
Currently at 95%+ function with a few residual withdrawal artifacts: tinnitus, chronic headache, low dopamine. I am back to "normal", but I have a palpable 'different' feeling of myself compared to before I started this adventure, but that was 4 years ago and certainly the passage of time alone has an effect
ThisMoment 4/3/14
I have a constant headache, tinnitus, and fatigue. My level of depression is about the same as when I started Cymbalta.
Phillyguy1 4/24/14
....being off in that 8-10 week window. I pretty much went off cold turkey. I've experienced similar with good and bad days. My biggest issue has been acute vertigo and tinnitus in my right ear. Some days it's been better than others for sure.
Sodone61 4/24/14 Off 5 weeks
No more paresthesia and headaches and the tinnitus (both ears, bad) is gone.
FiveNotions 4/24/14
Tinnitus...I hadn't thought about it in weeks....which meant I haven't had much of it (cymbalta gave it to me big time)....then, just this afternoon, kaboom....it's back, and with a vengeance....sounds like I've got a toilet flushing, sink running, and crickets chirping simultaneously inside my head....when I had it all the time I learned to ignore it....then, when it went away, I was astonished at being able to hear clocks tick and birds sing....now it's driving me nuts because Ive forgotten how to ignore it....it's gonna keep me awake tonight for sure....
Xman 4/25/14
Mine is much better, although I still have it in my right ear intermittently. I am intrigued that there is a pattern forming regarding the right ear tinnitus...
My tinnitus started during crapalta. Never had it before and have no inner ear problems whatsoever. My right ears--
Hickupp 5/8/14
Sorry Clara but at least for me it has never gone away and I've been off for several years. It doesn't happen every day but it still happens.
Clara 6/18/14 6 to 8 months off.
FINALLY coming alive again! And the tinnitus seems to have mostly GONE AWAY!!!!! So grateful about that!!!!
Xman 5/25/14
Thankfully. Also the buzzing in my ears and tinnitus like noise is less in severity. I am a little over 3 months post crapalta.
ThisMoment 5/5/14
After 42 days of tapering off by bead-counting, I swallowed my last bead on July 31, 2012. That was 22 months ago (approximately 660 days)!
I have two lingering side-effects that are probably permanent-- tinnitus in my right ear, and a constant (24/7) tension-type headache that I've had since i began the withdrawal more than two years ago
Must read...
http://www.cymbaltaw...om/?hl=tinnitus
Downtongirl 6/29/14 dw
Lots of ear pressure, pain, and the already existing tinnitus that I have developed from benzo tolerance/withdrawal was worse.
Downtongirl 7/3/14 dw
I developed tinnitus/hyperacusis last summer from what I believe to be tolerance withdrawals from klonopin but this Cymbalta makes it much worse. Anyone else experience this?
FiveNotions
As for the tinnitus, oh yeah, that was one of my long lasting effects....it got much much worse during the first weeks of withdrawal...then it almost disappeared, and I got all excited because I could hear my kitchen clock ticking....never knew it did that!....but then it came back.....it's faded a bit, and comes and goes....
MichB 7/7/14 dw
Oh yes! I have tinnitus too. If there is other noise around me it's not so bad but I can still hear it. Anytime it's quiet it sounds like an attack of locusts!! It's irritating but sadly I'm used to it. If its one of the few lasting permanent effects from getting off this poison I'll be fine.
Gail 7/21/14 5 months off
Tinnitus, which I can tolerate and on and off headaches that I can handle.
brzghoff 7/30/14 11 weeks off
For me getting off C has been rough, for the first month and a half or so it was a lot of physical stuff, joint and muscle pain - lots - serious gastro issues, nausea, the runs, etc, confusion, tinnitus.
Guest_Notsureaboutit_* 8/2/14 1 week off
Ears Whirring, Like A I Have A Helicopter In Them.
Response by Donewithcrap 8/2/14 Off
I have ringing in both ears and have had this for years now. I gets worse at tines but never goes away. I have tried "Ring Stop" but it didn't help me.
Response by ShadyLady 8/3/14 Off
I had the 'whirring swooshies' (great description!) for about 3 weeks after stopping the C-dope!
Pheobster 8/3/14 dw
Tinnitus has set in. Not super loud but enough to be another irritant.
tomitsu 9/2/14 off
I have anxiety and depression I didn't have before taking cymbalta. I have tinnitus and suicidal ideation is a reality. I have memory loss. I believe my symptoms are permanent as they have not gone away. I'm deeply disturbed by the symptoms.
nerdluvin 10/13/14 3 days off
For the past couple of weeks, I get intense migraine-level headaches (no brain zaps) and tinnitus in my ears.
FiveNotions 10/13/14 Off 10 months
I had tinnitus ... actually, after 10 months off, I still have it ... think it's permanent, due to the cold turkey
Thread Titile - Off Crapalta 6 Mos. Or More - What Symptoms Do You Still Have? 10/15/14
FiveNotions - 8 months off - The tinnitus returned several months ago, and is even louder and more constant than ever.
Clara - Tinnitus comes and goes, much less intense.
Gail - 8 mths - Tinnitus
Thisbetterpass 10/17/14
Looking back, I did start having problems with tinnitus when they switched me over to generic probably about two years ago.
Downtongirl 11/20/14 Off
I have developed tinnitus about 1 1/2 years ago and don't want to take anything to make that worse and nsaids are listing as being ototoxic...
FiveNotions 12/6/14 1 yr off
I am (so far) left with some apparently long-lasting after effects ... severe tinnitus,....
Shouldclean 3/31/15 3 mths off
Over a years time I weaned from 60 mg to 0. I was due to finish the end of January and was weighing the microscopic beads of 20 mg pills. I was in so much muscle pain that my husband suggested I go cold turkey, which I did on Christmas Day. My pain almost immediately was cut by 75%. I also had dizziness and tinnitus.
Sfava987 6/18/15
But after stopping the 20mg, I had the full blown discontinuation syndrome and could not drive or function. So, I went back on the 20mg and stayed there for a couple months, but the Tinnitus and some brain fog remained along with burning pain in my heels and the bottom of my feet.
ThisMoment 8/1/15 3 years off
I still have short-lived events that feel like ripples of withdrawal, and I still have a few symptoms that continue to fade: tinnitus, headache, unsteady balance, and GI instability
Things that list tinitus as a common symptom during dicontinuation;
Benzos
Coffee
Alcohol
Opium
SSRI
SNRI
Bath Salts
Dilantin and more...
Seven complete articles on treating tinitus.
Each link is followed by the title of the article in bold.
Articles concerning rTMS have the word "note" in front of the title.
https://www.ncbi.nlm...les/PMC4637057/
Note - Efficacy and Safety of Repeated Courses of rTMS Treatment in Patients with Chronic Subjective Tinnitus.
"Repeated application of rTMS seems to be useful in tinnitus management and should preferentially be offered to patients who experience a worsening of their tinnitus during the intertreatment interval, irrespective of their response to the first treatment course."
https://www.ncbi.nlm...les/PMC4678896/
Note - Combined rTMS treatment targeting the Anterior Cingulate and the Temporal Cortex for the Treatment of Chronic Tinnitus.
"This pilot study demonstrated the feasibility of combined mediofrontal/temporoparietal-rTMS-stimulation with double cone coil in tinnitus patients but failed to show better outcome compared to an actively rTMS treated control group."
https://www.ncbi.nlm...les/PMC4772792/
Note- Triple-site rTMS for the treatment of chronic tinnitus: a randomized controlled trial.
"We report a tendency towards a modest, sustained long-term effect of the triple-site stimulation protocol in comparison to the single-site protocol."
Table 2
Adverse events for both treatment groups.
single-site rTMS triple-site rTMS
transient adverse events
muscular tension 1 -
headache 6 3
blurred vision 1 -
increase in tinnitus loudness 3 -
mood swings 1 -
dizziness - 1
feeling of heaviness in the legs - 1
ongoing adverse events
increase in tinnitus loudness 3* -
broadening of the frequency range of the tinnitus - 1
/pmc/articles/PMC4772792/table/t2/?report=objectonly
*One of those three patients dropped out after two days of treatment.
https://www.ncbi.nlm...les/PMC2832848/
Emerging pharmacotherapy of tinnitus
Summary og medicines used for tinitus.
https://www.ncbi.nlm...les/PMC3563643/
Note - rTMS Induced Tinnitus Relief Is Related to an Increase in Auditory Cortical Alpha Activity
"Several studies indeed show tinnitus relief after rTMS, however effects are moderate and vary strongly across patients."
https://www.ncbi.nlm...les/PMC3227628/
Treatment options for subjective tinnitus: Self reports from a sample of general practitioners and ENT physicians within Europe and the USA
"A structured online questionnaire was conducted with 712 physicians who reported seeing at least one tinnitus patients in the previous three months. They were 370 general practitioners (GPs) and 365 ear-nose-throat specialists (ENTs) from the US, Germany, UK, France, Italy and Spain."
"Despite a large variety of treatment options, the low success rates of tinnitus therapy lead to frustration of physicians and patients alike. For subjective tinnitus in particular, effective therapeutic options with guidelines about key diagnostic criteria are urgently needed."
https://www.ncbi.nlm...les/PMC4761664/
Sensorineural Tinnitus: Its Pathology and Probable Therapies
"The most common form of treatment of tinnitus is pharmacological agents and behavioral treatment combined with sound therapy. Less common treatments are hypnosis and acupuncture. Various forms of neuromodulation are becoming in use in an attempt to reverse maladaptive plastic changes in the brain."
Summaries of articles on treating tinitis.
https://www.ncbi.nlm...pubmed/26960786
Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study.
"This pilot study highlights the significant prevalence of Vitamin B12 deficiency in North Indian population and improvement in tinnitus severity scores and VAS in cobalamin-deficient patients receiving intramuscular Vitamin B12 weekly for 6 weeks further provides a link between cobalamin deficiency and tinnitus thereby suggestive of a therapeutic role of B12 in cobalamin-deficient patients of tinnitus. "
http://www.ncbi.nlm..../pubmed/8484483
Vitamin B12 deficiency in patients with chronic-tinnitus and noise-induced hearing loss.
"These observations suggest a relationship between vitamin B12 deficiency and dysfunction of the auditory pathway. Some improvement in tinnitus and associated complaints were observed in 12 patients following vitamin B12 replacement therapy. The authors recommend that routine vitamin B12 serum levels be determined when evaluating patients for chronic tinnitus."
https://www.ncbi.nlm...les/PMC3645155/
The Role of Plasma Melatonin and Vitamins C and B12 in the Development of Idiopathic Tinnitus in the Elderly
"Comparing the plasma levels of the markers between elderly with and those without tinnitus, the plasma levels of melatonin (p=0.01) and vitamin B12 (p=0.03) were significantly lower among the elderly with tinnitus compared to those without, while the difference in the plasma level of vitamin C (p=0.6) was not.)
https://www.ncbi.nlm...les/PMC4765244/
Tinnitus: Is there a place for brain stimulation?
Nothing "to support or discourage the application of brain stimulation in tinnitus."
https://www.ncbi.nlm...pubmed/26938213
Electroacupuncture for Tinnitus: A Systematic Review.
"Due to the poor methodological quality of the primary studies and the small sample sizes, no convincing evidence that electroacupuncture is beneficial for treating tinnitus could be found. "
https://www.ncbi.nlm...pubmed/26910854
Randomized Controlled Trial of a Perceptual Training Game for Tinnitus Therapy
"The results suggest that the attention training game may have reduced focus on the tinnitus, potentially through improved selective attention. "Terrain" was superior to "Tetris" in the population tested and therefore shows promise as a management option for tinnitus. Further testing in a larger, more general, population would be enabled through improving the game's accessibility."
https://www.ncbi.nlm...pubmed/26901425
Cortical Reorganisation during a 30-Week Tinnitus Treatment Program.
https://www.ncbi.nlm...pubmed/26890094
Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus.
"In our study, verum cTBS was not superior to sham which highlights the persistent need for improving non-invasive brain stimulation techniques for the treatment of tinnitus."
https://www.ncbi.nlm...pubmed/26868680
Maladaptive plasticity in tinnitus - triggers, mechanisms and treatment
"Maladaptive neural plasticity seems to underlie these changes: it results in increased spontaneous firing rates and synchrony among neurons in central auditory structures, possibly generating the phantom percept. This Review highlights the links between animal and human studies, and discusses several therapeutic approaches that have been developed to target the neuroplastic changes underlying tinnitus."
https://www.ncbi.nlm...pubmed/26867083
Internet-Delivered Cognitive-Behavior Therapy for Tinnitus: A Randomized Controlled Trial
"Using a randomized controlled trial design, we replicated prior findings regarding positive effects of Internet-delivered CBT on tinnitus-related distress and associated symptoms."
https://www.ncbi.nlm...pubmed/26817797
Note -Long-Term Distributed Repetitive Transcranial Magnetic Stimulation for Tinnitus: A Feasibility Study.
"Our study demonstrated that rTMS can be delivered in a distributed schedule that is well-tolerated, feasible and may prove to be clinically beneficial. A long-term distributed rTMS schedule for tinnitus may warrant investigation as an alternative to the short-term aggregated treatment schedules more frequently used previously. For the many varied therapeutic uses of rTMS (established and investigational), treatment schedules are relatively unexplored, and deserve further attention."
https://www.ncbi.nlm...pubmed/26790209
[Deep needling and shallow needling at three acupoints around ear for subjective tinnitus: a randomized controlled trial].
"Acupuncture at the three acupoints around ear deeply could apparently improve tinnitus, and reduce tinnitus sound levels for subjective tinnitus. The effect is better than that by shallow needling at the three acupoints."
https://www.ncbi.nlm...pubmed/26773752
Auditory and visual 3D virtual reality therapy as a new treatment for chronic subjective tinnitus: Results of a randomized controlled trial.
"Virtual Reality appears to be at least as effective as CBT in unilateral subjective tinitus patients."
https://www.ncbi.nlm...pubmed/26771015
Feasibility and Safety of Transcutaneous Vagus Nerve Stimulation Paired with Notched Music Therapy for the Treatment of Chronic Tinnitus.
"After 10 treatment sessions, 15/30 patients (50%) reported symptom relief."
"This study has demonstrated the feasibility and safety of tVNS paired with notched music therapy in patients with chronic tinnitus, with the use of a pad-type electrode attached to the auricular concha."
https://www.ncbi.nlm...pubmed/26747828
Tinnitus and its current treatment-Still an enigma in medicine.
"As yet, there are no Food and Drug Administration approved drugs available and the quest for a new treatment option for tinnitus focus on important challenges in tinnitus management. A number of options have been used to treat patients with tinnitus, but outcomes have been limited."
https://www.ncbi.nlm...pubmed/26649534
Clinician-Supported Internet-Delivered Psychological Treatment of Tinnitus
"For the 6 studies comparing Internet treatment against a no-treatment control condition, a moderate effect size was found (Hedges's g = 0.58). The 3 studies comparing Internet treatment against face-to-face group treatments showed a small difference."
https://www.ncbi.nlm...pubmed/26632254
The efficacy of individual treatment of subjective tinnitus with cognitive behavioural therapy.
https://www.ncbi.nlm...pubmed/26619701
[Therapeutic perspectives in the treatment of chronic subjective tinnitus].
"There are no effective therapies for the treatment of chronic subjective tinnitus. The present study aims to compare two therapeutic approaches: Tinnitus Retraining Therapy (TRT) and a Biopsychosocial Approach (BPS). Results show no difference in evolution of tinnitus' perception between the beginning of the study and after 12 months of treatment in both treatment groups."
https://www.ncbi.nlm...pubmed/26609769
Potassium channels as promising new targets for pharmacologic treatment of tinnitus: Can Internet-based 'crowd sensing' initiated by patients speed up the transition from bench to bedside?
https://www.ncbi.nlm...pubmed/26557055
Note - Repetitive transcranial magnetic stimulation induces oscillatory power changes in chronic tinnitus.
"This is the first study to show tinnitus-related alterations of neuroplasticity that were specific to stimulation site and oscillatory frequency."
"Moreover our findings confirm the role of the left temporal and the right frontal areas as relevant hubs in tinnitus related neuronal network. Our results underscore the value of combined TMS-EEG measurements for investigating disease related changes in neuroplasticity."
https://www.ncbi.nlm...pubmed/26547700
Antioxidant therapy in the elderly with tinnitus.
Prospective, randomized, double-blinded, placebo-controlled clinical trial. The sample consisted of 58 subjects aged 60 years or older, with a complaint of tinnitus associated with sensorineural hearing loss. The treatment regimens were: Ginkgo biloba dry extract (120mg/day), α-lipoic acid (60mg/day)+vitamin C (600mg/day), papaverine hydrochloride (100mg/day)+vitamin E (400mg/day), and placebo.There was no benefit from the use of antioxidant agents for tinnitus in this sample.
https://www.ncbi.nlm...pubmed/26541232
Effectiveness of sound therapy in patients with tinnitus resistant to previous treatments: importance of adjustments.
"There was improvement in quality of life (Tinnitus Handicap Inventory), with good response to sound therapy using customized settings in patients who did not respond to previous treatments for tinnitus."
https://www.ncbi.nlm...pubmed/26498289
Repeated sessions of transcranial direct current stimulation for treatment of chronic subjective tinnitus: a pilot randomized controlled trial.
"No statistically significant difference was found between anodal and sham stimulation regarding either immediate or long-lasting effects over the 2 weeks follow-up period. Deterioration of symptoms and alteration in tinnitus characteristics were reported by a few patients. There were no significant long-term beneficial effects following tDCS of the left temporoparietal area. "
https://www.ncbi.nlm...pubmed/26467416
The Management and Outcomes of Pharmacological Treatments for Tinnitus.
Table 1.
Pharmaceutical treatment effects on tinnitus.
Drugs Authors Subjects Placebo Controlled Dosage Results Side Effects
Lidocaine Melding,
et al. (1978) 78 Open-label 1-2 mg per kg of body weight intravenously for 3-4 minutes Highly effective in patients with Organ of Corti damage None
Nortriptyline Sullivan
et al. (1989) 19 Placebo-washout Maximum 50 to 150 mg per day Tinnitus loudness and severity decreased Dry mouth, dyspepsia, constipation, orthostatic hypotension
Sullivan
et al. (1993) 92 Placebo controlled 50 to 150 mg/mL for six weeks Depression and tinnitus loudness decreased Anticholinergic side effects, sedation
Amitriptyline Podoshin
et al. (1995) 218 Placebo controlled 10 mg 3x/day for 10 weeks Improvement in more than 40% Sedation
Bayar et al. (2001) 37 Placebo controlled 50 to 100 mg daily for six weeks Decreased tinnitusintensity and subjective relief Sedation, dryness of mouth
Mendis
et al. (2008) 1 Case study 10 mg for three days Neurologic foot pain resolved Tinnitus
Imipramine Tandon
et al. (1987) 475 Chart review 150 to 250 mg per day Depression improved Tinnitus
Evans et al. (1981) 1 Case study 15 to 45 mg per day No improvement in depression Tinnitus
Sertraline Zoger et al. (2006) 76 Placebo controlled 25 to 50 mg daily for 16 weeks Improved loudness, severity Sexual side effects
Paroxetine Robinson
et al. (2005) 115 Placebo controlled Maximum of 50 mg per day for 100 days No better than placebo Sexual dysfunction, drowsiness,
dry mouth, sweating,
insomnia, gastrointestinal distress, tremor, headache
Alprazolam Johnson
et al. (1993) 36 Placebo controlled 0.25 or 0.5 mg for one week, increased to maximum of 1.0 mg for some for 56 days Reduction in loudness Excessive drowsiness; more dreams
Jalali et al. (2009) 36 Placebo controlled 0.5 mg 1-3 times per day for 8 weeks No improvement None
Clonazepam
Ginkgo biloba Han et al. 2012) 38 Open-label 0.5 mg Clonazepam; 4.0 mg GB increased from 1 to 4 doses per day for 5 weeks Clonazepam more effective than GB; tinnitus annoyance, duration, and loudness decreased Drowsiness
Gabapentin Bauer et al. (2006) 39 Placebo controlled Maximum 2,400 mg for 20 weeks Decrease in annoyance Dizziness, fatigue
Witsell et al. (2006) 76 Placebo controlled 1800 mg daily for five weeks No significant difference Mouth sores, decreased libido
Amino-oxyacetic Acid Reed et al. (1985) 10 Placebo controlled 50 to 75 mg four times a day for one week Subjective lessening of tinnitus in 3/10 Worsening of tinnitus upon withdrawal; dizziness, lightheadedness, disequilibrium, nausea, and headache at higher doses (400 mg/day)
Lamotrigine Simpson
et al. (1999) 31 Placebo controlled 25 to 100 mg daily for 8 weeks No significant difference Nausea, vomiting, headache
Carbamazepine Donalson I (1981) 62 Placebo controlled 100 mg No significant difference Tinnitus returned rapidly post-injection
Memantine Figueiredo
et al. (2008) 43 Placebo controlled 5 to 10 mg 1-2 times per day for 90 days No significant difference Dizziness, high blood pressure, insomnia, stomachache
Flupirtine Salembier
et al. (2006) 24 Open-label 100 mg twice a day for three weeks No significant difference Amnesia and concentration disorders
Neremexane Suckfull et al (2011) 320 Placebo controlled 25 to 75 mg daily for 16 weeks Decreased annoyance and impact on life at higher dosage Dizziness, headache, vertigo, fatigue, hypertension
Acamprosate Azevedo et al. (2007)
Sharma et al. (2012) 50
40 Placebo controlled
Placebo controlled 333 mg 3x daily for
three months
333 mg TDS 3x daily
for 45 days Improvement
over placebo
Significant improvement over placebo Epigastralgia, choking
Worsening intensity
(2 participants)
Cyclobenzaprine Coelho at al. (2011) 49 open-label max high dose: 30 mg; max low dose: 10 mg high dosage saw a reduction in THI dry mouth, sleepiness, constipation
Vanneste et al. (2013) 95 open-label 10 mg 2x/day for 4 weeks reduction in distress and intensity worsening intensity
Naltrexone Vanneste et al. (2013) 106 open-label up to 50 mg for four weeks tinnitus distress reduced in some none
Deanxit Meeus et al. (2011) 28 placebo-controlled 1 mg per day for three weeks 3/28 report tinnitus improvement none
Betahistine Sonmez et al. (2013) 68 placebo-controlled 48 mg per day for three months slight improvement in loudness and on THI pyrosis, nausea
Pramipexole Sziklai et al. (2011) 40 placebo-controlled maximum dosage: 0.7 mg 3x/day for 4 weeks 35% of pramipexole group improved dizziness, allergic reactions
Piribedil De Azevedo
et al. (2009) 56 Placebo-controlled 50mg daily No difference from placebo Nausea, dizziness
Simvastatin Canis et al. (2011) 94 placebo-controlled 40 mg/day for 4 months reported improvement but not significant worsening tinnitus
Vitamin B12 Berkiten et al. (2013) 83 placebo-controlled 1 g/mL injected daily for 5 days, then once a month for 12 months no significant change N/A
Zinc Coelho et al. (2013) 89 placebo-controlled 220 mg zinc sulphate daily for 4 months no significant change indigestion
https://www.ncbi.nlm...pubmed/26459345
Slow Cortical Potential Neurofeedback in Chronic Tinnitus Therapy: A Case Report.
https://www.ncbi.nlm...pubmed/26433054
Cannabinoids, cannabinoid receptors and tinnitus.
https://www.ncbi.nlm...pubmed/26430749
Note - A Pilot Study of EEG Source Analysis Based Repetitive Transcranial Magnetic Stimulation for the Treatment of Tinnitus.
"Low-frequency rTMS decreased tinnitus significantly after active, but not sham, treatment. Responders in the EEG source analysis-based rTMS group, 71.4% (5/7) patients, experienced a significant reduction in tinnitus loudness, as evidenced by VAS scores. The target site of neuronal generators most consistently associated with a positive response was the frontal lobe in the right hemisphere, sourced using high-density EEG equipment, in the tinnitus patients. After left temporoparietal rTMS stimulation, 42.8% (3/7) patients experienced a decrease in tinnitus loudness."
https://www.ncbi.nlm...pubmed/26422238
The effect of noninvasive brain stimulation on neural connectivity in Tinnitus: A randomized trial.
"Sixteen patients received active rTMS treatment; 14 patients received sham treatment. There were no differences between the active and sham groups in baseline functional connectivity. Neither treatment with rTMS nor sham therapy resulted in statistically significant functional connectivity changes in the examined brain networks."
https://www.ncbi.nlm...pubmed/26413574
The Effect of Korean Red Ginseng on Symptoms and Quality of Life in Chronic Tinnitus: A Randomized, Open-Label Pilot Study.
"Fifty-nine patients completed the planned protocol. Significant improvements were observed between initial and post-treatment THI scores in patients receiving 3000 mg/day KRG. Treatment with 3000 mg/day KRG for 4 weeks significantly improved role emotional and mental health scores in the SF-36 survey.These results suggest that KRG may improve tinnitus symptoms and mental wellbeing in chronic tinnitus patients."
https://www.ncbi.nlm...pubmed/26406286
An evaluation of the Reltus ear massager for short-term tinnitus relief.
'Supression of tinitus loadmess to auditory stimulation was found in 87% of participants and to tactile stimulation in 83%. No significant differences were found in the effectiveness between the four vibration stimulation points, or between the left and right ear of the participants. The Reltus produced a sound that resulted supression of tinitus.'
"It is the auditory artifact of the Reltus that was responsible for short-term tinnitus suppression."
This device rates a 2.5 out od 5 stars on Amazon.
https://www.ncbi.nlm...pubmed/26388055
The Development of Acceptance of Chronic Tinnitus in the Course of a Cognitive-Behavioral Group Therapy.
"CBT is considered an effective treatment for tinnitus distress in patients with chronic tinnitus. Acceptance of chronic tinnitus clearly improved within a CBT group therapy."
https://www.ncbi.nlm...pubmed/26261868
Treatment of tinnitus.
https://www.ncbi.nlm...pubmed/26248783
The effectiveness of psychological interventions among tinnitus sufferers: A review.
"Psychological interventions were more effective in reducing psychological impacts of tinnitus than non-psychological interventions such as the use of tinnitus maskers. Nevertheless, the combination of the treatments yielded more superior outcomes."
http://www.cymbaltaw...lped#entry71820
and
http://www.cymbaltaw...elps#entry65067
Research and treatments for tinnitus.
http://www.cymbaltaw...rove#entry72117
Information on tinnitus.
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Restless Leg Syndrome
(Synopsis from PubMed)
Causes
Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the The substantia nigra plays an important role in reward, addiction, and movement and is composed of dopaminergic neurons. This area is one of the primary areas for the production of dopamine. Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine and adrenaline.
Magnesium deficiency.
Magnesium deficiency showed important disorders of sleep organization, agitated sleep with frequent periods of nocturnal awakenings, increase of the durations and percentages of light sleep, a decrease of duration and percentage of deep sleep, a decrease of duration and percentage of REM sleep caused by magnesium deficiency with the disappearance in the REM sleep in some.
Iron Deficiency
The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L), which accounts for just over 20% of all cases of RLS. Normal blood levels are 30-300 ng/mL for males and 15-200 ng/mL for females. Studies using cerebrospinal fluid, magnetic resonance imaging, ultrasound determination of iron and autopsy tissue have implicated a primary role for brain (substantia nigra) iron insufficiency in restless legs syndrome (RLS). Ferritin can deliver iron to multiple organs, including the brain. The data clearly show changes in iron status affect dopaminergic activity. The proposed etiology of RLS is the central dopaminergic dysfunction, based on the benefits of dopamine agonists and exacerbation of RLS symptoms by dopaminergic antagonists.
Iron is most available to the body when chelated to amino acids - iron in this form is ten to fifteen times more bioavailable than any other, and is also available for use as a common iron supplement. Often the amino acid chosen for this purpose is the cheapest and most common amino acid, glycine, leading to "iron glycinate" supplements. RDA for iron varies considerably based on age, gender, and source of dietary iron (heme-based iron has higher bioavailability).
Iron uptake is tightly regulated by the human body, which has no regulated physiological means of excreting iron. Only small amounts of iron are lost daily due to mucosal and skin epithelial cell sloughing, so control of iron levels is mostly by regulating uptake.[33] Regulation of iron uptake is impaired in some people as a result of a genetic defect that maps to the HLA-H gene region on chromosome 6. In these people, excessive iron intake can result in iron overload disorders, such as hemochromatosis. Many people have a genetic susceptibility to iron overload without realizing it or being aware of a family history of the problem. For this reason, it is advised that people do not take iron supplements unless they suffer from iron deficiency and have consulted a doctor. Hemochromatosis is estimated to cause disease in between 0.3 and 0.8% of Caucasians.[34]
Certain medications may worsen RLS in those who already have it, or cause it secondarily. These include: any antidepressants (SSRIs).
Genetics
More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.
Six genetic loci found by linkage are currently known and are listed below.
12q,14q, 9p, 20p, 2p and 16p12.1.
Four genes, MEIS1, BTBD9, PTPRD and MAP2K5, were found to be associated to RLS.
Effects
Sleep - For 60%–80% of patients with RLS, sleep disturbance is their most distressing symptom. For example, impact on patients’ daytime cognitive abilities, patients report reduced concentration and attention, increased daytime sleepiness, and mood disturbance. Studies have indicated that the symptoms of RLS precede those of depression or anxiety, and others relate the severity of mood symptoms to the severity of RLS symptoms. For some patients, the effects on mental health may be so pronounced as to reach the diagnostic criteria for major depressive disorder or generalized anxiety disorder
Several studies have shown an association between the symptoms of RLS and worse mental health. The authors concluded that the presence of RLS symptoms “was probably the major determining factor for the anxiety and depression scores, with higher scores correlating with more severe RLS”.
Diagnosis
Serum ferritin levels are measured in patients as part of the iron studies workup for anemia and for restless legs syndrome. The ferritin levels measured have a direct correlation with the total amount of iron stored in the body including cases of anemia of chronic disease.
Normal blood levels are 30-300 ng/mL for males and 15-200 ng/mL for females.
Treatment
Patients with RLS and prominent anxiety symptoms may require treatment with an anxiolytic in addition to dopaminergic therapy for the RLS symptoms. The benzodiazepines have been used in the treatment of RLS. Their efficacy depends mostly on reducing insomnia, rather than managing the motor and sensory symptoms of RLS. These drugs may be useful in the management of RLS and anxiety, though there are concerns about the long-term use of these agents and patients require monitoring for dependency and declining efficacy.
Iron supplements - People with RLS should have their ferritin levels tested; ferritin levels should be at least 50 µg for those with RLS. Oral iron supplements, taken under a doctor's care, can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms. A ferritin level of 50 µg is not sufficient for some sufferers and increasing the level to 80 µg may greatly reduce symptoms. However, at least 40% of people will not notice any improvement. It is dangerous to take iron supplements without first having ferritin levels tested, as many people with RLS do not have low ferritin and taking iron when it is not called for can cause iron overload disorder, potentially a very dangerous condition.
RDA – 8 mg/day; UL 45 mg/day One used 200 mg ferrous sulfate 3 times per day, which equals 73.5 mg iron 3 times per day or 225 mg/day. An additional study used 7 mg of iron/day. They used iron succinylate or bisglycinate
Clonidine - Patients subjectively reported improvement in leg sensations and motor restlessness while receiving clonidine (0.05 mg/day). Sleep onset occurred faster with clonidine (12 minutes) compared with placebo (30 minutes) and baseline (47 minutes). Adverse findings with clonidine treatment included decreased REM sleep in the clonidine group (4%) compared with placebo (16%) and baseline (16%) and increased REM delay in the clonidine group (195 minutes) compared to the placebo (70 minutes) and baseline groups (89 minutes) There was a nonstatistical trend toward an increase in stage 3 and 4 sleep and a decrease in motor activity. Clonidine may be an effective treatment for RLS patients who don't have large numbers of sleep-disrupting periodic limb movements but have delayed sleep onset due to leg sensations and
An additional double-blind study was conducted in 20 patients with renal failure and symptoms of restless legs. 10 patients were treated with 0.075 mg clonidine twice daily and 10 received placebo. Three days after starting therapy. the clonidine-treated group complete relief of symptoms was noted in 9 out of 10 patients.
Gabapentin - Gabapentin, an analog of gamma-aminobutyric acid, was compared with L-dopa in a small, open-label study involving patients with RLS secondary to renal disease. After 4 weeks, both treatments improved the symptoms of RLS. Gabapentin produced significant improvements compared with baseline on three of the eight SF-36 domains. Gabapentin produced adverse events of malaise (feeling bad) and somnolence (drowsiness); but resulted in no patient withdrawal.
Magnesium/Calcium– RDA 400 mg/day Serum levels should be between .7 and 1 mmoles/L. Studies used 400 – 800 mg/day. (avg. 600 mg/day; 6 tablets) Special note - Amino Acid Magnesium most readily absorbed form of magnesium and most tolerated by the gi tract.
Studies recommend using 600 to 1,000 mg calcium with the magnesium. (800 mg/day avg.; ) RDA 1,000 mg/day, UL 2500 mg/day. The individual must allow for dietary intake. As calcium and magnesium compete in the blood system you should also have your serum calcium and magnesium nmonitored every 6 months.
Magnesium availability different Mg-sources
Mg-source Mg-content % Rel. Biological value % Rel. Available Mg g/kg
Mg-Chloride 12 89 107
Mg-Hydroxide 36 99 356
Mg-Phosphate 26 85 221
Mg-Ca-Phosphate 9 91 82
Mg-Ca-Na Phosphate 5 94 47
Mg-Oxide, granular 51 61 311
Mg-oxide, powder 51 84 428
MG-Sulphate 10 96 96
Source: EMFEMA 2002
Folic Acid – Recommended to be taken, no research to back this. Use folic acid at 4 – 10 mg/day.
http://www.cymbaltaw...rls/#entry72695
Detailed information on Restless Leg Syndrome
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Cymbalta and Pregnancy
http://www.ncbi.nlm....pubmed/23471302
No significant effect on fetus.
http://www.ncbi.nlm....pubmed/21359876
Low amount of cymbalta across placenta and in lactation.
http://www.ncbi.nlm....pubmed/23218163
Text not available.
http://www.ncbi.nlm....pubmed/23873363
No effects on new born health.
http://www.ncbi.nlm....pubmed/19809008
No effect on fetus, newborn at birth or during lactation.
http://www.ncbi.nlm....les/PMC3590601/
List what the negative out comes are.
http://www.ncbi.nlm....pubmed/25171134
Increase risk of club foot with ssri.
http://www.bmj.com/c.../bmj.g4835.long
SSRI increase risk of autism in new borns.
https://www.ncbi.nlm...pubmed/25551238
Little transferred to infant.
Duloxetine withdrawal syndrome in a newborn
http://cpj.sagepub.c...52/10/976.short
Clinical presentation and management of neonatal abstinence syndrome
http://www.dovepress...hp?fileID=19621
Use of selective serotonin reuptake inhibitors during pregnancy
http://contemporaryo...nancy?page=full
Neonatal paroxetine withdrawal syndrome
http://www.ncbi.nlm....les/PMC1721229/
Four term neonates presented with symptoms such as jitteriness and necrotising enterocolitis after paroxetine exposure in utero.
The use of psychotropic medication during pregnancy: how about the newborn?
http://www.ncbi.nlm....les/PMC3770341/
http://www.cymbaltaw...tion#entry40047
Info on Cymbalta and pregnancy
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Cymbalta and the Heart
https://www.ncbi.nlm...pubmed/27130441
Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.
https://www.ncbi.nlm...pubmed/23666493
"Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of duloxetine overdose and when administering duloxetine to patients susceptible to drug-induced QT prolongation."
https://www.ncbi.nlm...pubmed/23422380
"In conclusion, in healthy adults exposed to DLX (Cymbalta) or ESC, no clinically significant effects on HRV (heart rate variability) were observed."
https://www.ncbi.nlm...pubmed/22163139
Abstract
Takotsubo cardiomyopathy is characterized by transient multisegmental left ventricular dysfunction, dynamic electrocardiographic changes that mimic acute myocardial infarction, and the absence of obstructive coronary disease. Takotsubo cardiomyopathy has been solidly associated with antecedent emotional and physical stressors that trigger catecholamine surges, which lead to coronary vasospasm or direct myocardial injury. Some medications can also cause catecholamine surges, although this phenomenon is not as well described. Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor (SNRI). The basic goal of SNRIs is to increase catecholamine levels in neuronal tissue. However, the increased catecholamine levels may also affect the cardiovascular system.Herein, we report the case of a 59-year-old woman whose takotsubo cardiomyopathy was temporally associated with the titration of duloxetine. The duloxetine therapy was subsequently discontinued, and the patient's left ventricular function recovered completely 1 month after the index event. The purpose of this report is to alert clinicians to a possible association between SNRI medications and takotsubo cardiomyopathy.
https://www.ncbi.nlm...pubmed/18728105
Duloxetine-associated tachycardia
"Clinicians should be aware of the possibility of clinically significant tachycardia in patients receiving duloxetine, even in low doses."
https://www.ncbi.nlm...pubmed/18445706
Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy.
"Use of drugs that increase serum norepinephrine levels, such as the SNRIs, may be potentially deleterious in individuals with unstable or advanced HF. These medications should be avoided or used with caution and monitored regularly in this patient population."
https://dailymed.nlm...f2-c185fbad64ba
"Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia. "
Post Marketing reports - supraventricular arrhythmia,
http://www.cymbaltaw...tion#entry70794
Information on Heart conditions and Cymbalta
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Cymbalta and High blood pressure
http://dailymed.nlm....?archiveid=1526
This is a document from Eli Lilly that in it it links high BP to Cymbalta.
http://www.nlm.nih.g...ds/a604030.html
Medline plus includes a warning about high BP as well. Medline plus is a service of the Federal government.
http://www.ehealthme...pressure - high
This article is from ehealth. It monitors reported side effects to the FDA and other sites. Over 5% of the users of cymbalta report high bp.
http://www.ncbi.nlm....pubmed/16303903
http://www.ncbi.nlm....les/PMC3661232/
http://www.ncbi.nlm....les/PMC2646646/
http://www.ncbi.nlm....les/PMC3004624/
http://www.ncbi.nlm....les/PMC3437646/
Research articles documenting elevation of bp by Cymbalta.
http://www.fda.gov/d...y/ucm088579.pdf
http://www.accessdat...0/022516lbl.pdf
FDA warns of risk of high blood pressure. Second one includes a black box warning from 2010 on elevated BP.
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Cymbalta's Damages/Effects
Introduction - Cymbalta is a seratonin norepinephrine reupyale inhibitor (SNRI). It is mostly prescribed for major depressive disorder, generalized anxiety disorder, fibromyalgias and neuropathic pain. Duloxetine failed to receive US approval for stress urinary incontinence amid concerns over liver toxicity and suicidal events; however, it was approved for this indication in the UK, where it is recommended as an add-on medication in stress urinary incontinence instead of surgery.
Duloxetine inhibits the reuptake (reuse) of serotonin (5-HT) and norepinephrine (NE) in the central nervous system. Duloxetine increases dopamine (DA) specifically in the prefrontal cortex, where there are few DA reuptake pumps, via the inhibition of NE reuptake pumps (NET) which is believed to mediate reuptake of DA and NE. However, duloxetine has no significant affinity for dopaminergic, cholinergic, histaminergic, opioid, and GABA reuptake transporters and can therefore be considered to be a selective reuptake inhibitor at the 5-HT and NE transporters
Serotonin (5HT) is primarily found in the gastrointestional tract (GI tract), blood platelets, and the central nervous system (CNS). It is popularly thought to be a contributor to feelings of well-being and happiness. Serotonin action is terminated primarily by uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan, tricyclic antidepressants, selective seratonin reuptake inhibitors (SSRIs) and seratonin norepinephrine reuptake inhibitors (SNRIs).
Serotonin is released into the space between neurons (synapse) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
When humans smell food, dopamine is released to increase the appetite. The serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with increased weight gain, especially in people with a low number of receptors. ( Cymbalta and weight gain: https://www.ncbi.nlm...pubmed/25467076, https://www.ncbi.nlm...ubmed/24898363, https://www.ncbi.nlm...ubmed/21314871)
The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm (24 hour cycles up and down) which is characterised by a peak at morning when the motivation to eat is strongest.
In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2a receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by seratonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.
In the digestive tract
The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the digestive system. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.
If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptors trigger zone that stimulate vomiting.
Bone metabolism
Alterations in serotonin levels and signaling have been shown to regulate bone mass. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1b receptors, it negatively regulates bone mass, while it does so positively through 5-HT2b receptors and 5HT2c. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts (bone cells) culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders. No research has been done on the effects of Cymbalta on bone mass.
Organ development
Since serotonin signals resource availability it is not surprising that it affects organ development. Rodent experiment shows that neonatal exposure to SSRI's makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants.
Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2a and 5-HT2b, mediating liver compensatory regrowth. Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5HT2B receptors also activate osteocytes, which build up bone. However, serotonin also inhibits osteoblasts, through 5-HT1B receptors. (Cymbalta and liver damage; https://www.ncbi.nlm...les/PMC3773985/
https://www.ncbi.nlm...les/PMC3182394/
https://www.ncbi.nlm...pubmed/22772703
https://www.ncbi.nlm...bmed/21694615).
Cardiovascular growth factor
Serotonin, in addition, causes endothelial (the inside lining of blood and lymphatic vessels) nitric oxide synthase activation. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing. (Cymbalta slows clotting; https://www.ncbi.nlm...pubmed/22054632
https://www.ncbi.nlm...bmed/18958440.)
Norepinephrine also called noradrenaline (NA), is an chemical that functions in the human brain and body as a hormone and neurotransmitter.The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility. Norepinephrine can be converted by the body to epinephrine (adrenaline).
The sympathetic effects of norepinephrine include:
In the eyes, an increase in production of tears, making the eyes more moist., and pupil dilation through contraction of the iris dilator.
In the heart, an increase in the amount of blood pumped.
In brown adipose tissue, an increase in calories burned to generate body heat.
Multiple effects on the immune system. The sympathetic nervous system is the primary path of interaction between the immune system and the brain, and several components receive sympathetic inputs, including the thymus, spleen, and lymph nodes. However the effects are complex, with some immune processes activated while others are inhibited.
In the arteries, constriction of blood vessels, causing an increase in blood pressure.
In the kidneys, release of renin and retention of sodium in the bloodstream.
In the liver, an increase in production of glucose, either by glycogenolysis after a meal or by gluconeogenesis when food has not recently been consumed. Glucose is the body's main energy source in most conditions.
In the pancreas, increased release of glucagon, a hormone whose main effect is to increase the production of glucose by the liver.
In skeletal muscles, an increase in glucose uptake.
In adipose tissue (i. e., fat cells), an increase in lipolysis, that is, conversion of fat to substances that can be used directly as energy sources by muscles and other tissues.
In the stomach and intestines, a reduction in digestive activity. This results from a generally inhibitory effect of norepinephrine on the enteric nervous system, causing decreases in gastrointestinal mobility, blood flow, and secretion of digestive substances.
In the central nervous system norepinephrine is released by the locus coeruleus and affects brain function in a number of ways. It enhances processing of sensory inputs, enhances attention, enhances formation and retrieval of both long term and working memory, and enhances the ability of the brain to respond to inputs by changing the activity pattern in the prefrontal cortex and other areas. The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating effect.
Document #1
http://www.researchg...289a09b6b1a.pdf
Evaluation of Duloxetine as Micronuclei Inducer in an Acute and a Subchronic Assay in Mouse
Eduardo Madrigal-Bujaidar1), Isela Álvarez-González1), Eduardo Osiris Madrigal-Santillán2), José A Morales-González2)
Duloxetine is a widely used antidepressant worldwide. In the present report, we evaluated its capacity to induce micronucleated polychromatic erythrocytes (MNPEs) and micronucleated normochromatic erythrocytes (MNNEs) in mice. Two assays were performed, one with a single chemical administration and the other with daily chemical administration. In the first, we administered the antidepressant once to groups of 5 mice
by the intragastric (i.g.) route (2, 20, and 200 mg/kg) and performed the analysis at 24, 48, and 72 h postadministration. A control group administered i.g. distilled water was included in the assay, as well as another treated with the micronuclei-inducing chemical daunorubicin (2.5 mg/kg, injected intraperitoneally (i.p.)). In this assay, we found significant damage induced by duloxetine starting from the first time evaluated, showing the highest MNPE increase at the end of the assay. We observed a saturation effect as well, suggested by a decreasing relative efficiency with respect to each tested dose. In a second assay, we administered the antidepressant i.g. every day for 5 weeks (2, 6, and 12 mg/kg), and micronuclei analysis was performed at the end of each week. In this study, we also found a significant increase in both MNPEs and MNNEs which was clear by the second week of administration. Our results suggest that short-term as well as cumulative damage is produced by duloxetine. Thus, confirmation of the observed genotoxic potential in other models seems advisable, as well as caution when prescribing this antidepressant. Duloxetine, a potent serotonin and norepinephrine reuptake inhibitor which effectively desensitizes various autoreceptors and promotes neuroplasticity. The compound is used in stress urinary incontinence, and due to its analgesic efficacy it is also prescribed for chronic pain conditions such as diabetic
peripheral neuropathy, fibromyalgia, chronic low back pain,and osteoarthritis knee pain.
Translation -
Cymbalta causes the development of damaged red blod cells which may or may not benormal in color and have a very small nucleus (the nucleus contains the cells DNA).
Also, Cymbalta improves neuroplasticity. The brain's ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment. Brain reorganization takes place by mechanisms such as "axonal sprouting" in which undamaged axons grow new nerve endings to reconnect neurons whose links were injured or severed. Undamaged axons can also sprout nerve endings and connect with other undamaged nerve cells, forming new neural pathways to accomplish a needed function.
Cymbalta downregulates the activity of the bladder control nerves.
Document #2
https://www.ncbi.nlm...pubmed/18973814
Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models.
Pereira P1, Gianesini J, da Silva Barbosa C, Cassol GF, Von Borowski RG, Kahl VF, Cappelari SE, Picada JN.
Abstract
Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake, used in the treatment of major depression. It has been recognized that some antidepressants can affect memory in humans, but there is not study that report the duloxetine effect on memory using the inhibitory avoidance. The aim of this work was to investigate the effect of duloxetine on short- and long-term memory (STM and LTM) in the inhibitory avoidance task in mice. Duloxetine (10 and 20 mg/kg; i.p.) administered before or after the inhibitory avoidance training was not able to produce effects on STM e LTM (p>0.05). The group that received MK-801 (0.0625 mg/kg), an NMDA receptor antagonist, showed an impairment in STM and LTM (p<0.01). These effects were not reversed by duloxetine administration (p=0.114 and p=0.06, respectively). Duloxetine effect on memory 5 days after i.p. administration was also investigated. After this treatment both duloxetine doses used were unable to affect STM or LTM in the inhibitory avoidance task (p=0.371 and p=0.807, respectively). DNA damages were evaluated in brain tissues and blood by the comet assay, after subacute treatment (10 or 20 mg/kg by 5 days). Duloxetine did not induce genotoxic effects. However, when the cells were treated ex vivo hydrogen peroxide, a pro-oxidant effect on brain tissue from treated animals was observed with significantly higher DNA damage in comparison to untreated animals, suggesting increased susceptibility to injuries by reactive oxygen species in brain after treatment with duloxetine. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.
Translation - Cymbalta did not cause DNA damage.
Document #3
https://www.ncbi.nlm...les/PMC4713700/
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
(This study shows the direct effect of Cymbalta on miRNA (used in translating DNA code) in the hippocampus (one of the emotional centers in the brain). Duloxetine in particular has been reported to induce embryotoxicity in aquatic organisms.
Moreover, as no explanation has been proposed for DNA/chromosomal damage induced by duloxetine and other antidepressants, the detection of specific molecular lesions or
the involved biochemical routes is a matter of research.
Translation - RNA 'reads' the genes in the DNA and then produces the appropriate product. For example if a certain part of the DNA is for a digestive protein the RNA would actually copy that part of the DNA and then use that information to produce the desired protein. A microRNA ( miRNA) is a small RNA molecule that functions in stopping the RNA process and post-'copying' transcription mechanisms that are used by cells to increase or decrease the production of specific gene products (such as proteins or RNA). In simple terms Cymbalta regulates DNA product manufacturing in the frontal lobe and hippocampus.
The frontal lobe is located at the front of the brain contains most of the dopamine-sensitive neurons (nerve cells) in the cerebral cortex. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain.
The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is particularly important in forming new memories and connecting emotions and senses to memories. Because of this it is the center for memory based psychological learned responses (such as PTSD). It is also the center of the human fear circuits. The hippocampus receives input from neurotransmitter systems, including serotonin, norepinephrine, and dopamine systems. It also receives cholinergic input (responds to the neurotransmitter acetylcholine) from the medial septum, which regulates the hippocampal physiological state. The hippocampus is highly involved in sleep patterns including REM sleep. There is evidence that humans having experienced severe, long-lasting traumatic stress show atrophy (shrinking fur to lack of use) of the hippocampus more than of other parts of the brain.
Document #4
https://www.ncbi.nlm.../pubmed/9686935
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):600-10.
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
Rueter LE1, Kasamo K, de Montigny C, Blier P.
Abstract
Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - This research proves that Cymbalat affects the seratonin reuptake proteins. It also shows an increase in seratonin in the hippocampus and no change in seratonin in the frontal cortex. Other studies show that past the 2 month state seratonin levels drop with Cymbalta usage.
Document #5
https://www.ncbi.nlm...les/PMC3362535/
Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment
Francesca Calabrese,1 Gianluigi Guidotti,1 Raffaella Molteni,1 Giorgio Racagni,1,3 Michele Mancini,2 and Marco Andrea Riva1,3,*
Abstract
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
Translation - High glutamate (neurotransmitter) in the hippocampus contributes to depresssion. Cymbalta returns the glutamate gene function to normal activity in the hippocampus. Glutamate is an amino acid, one of the twenty amino acids used to construct proteins, and as a consequence is found in high concentration in every part of the body. In the nervous system it plays a special additional role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. In fact glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It is no wonder that Cymbalta can cause such varied side effects and withdrawal symptoms as it can potentially effect all nerve cells in the brain and nervous system.
Comment - Is it no wonder that Cymbalta has such a tremendous and varied effect on the human body while on the srug or during recovery/withdrawal afterward.
Document #6
J Biol Chem. 2014 Sep 5; 289(36): 25177–25185.
Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*
Eunice Y. Yuen,‡ Luye Qin,‡ Jing Wei,‡§ Wenhua Liu,‡ Aiyi Liu,‡ and Zhen Yan‡§,1
Abstract
The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of Gi protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.
Translation - Cymbalta, by affecting both seratonin and alpha adrenaline receptors, affects glutamate receptor signaling in the prefrontal cortex of the brain.
Document #7
https://www.ncbi.nlm...pubmed/26135544
Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity.
Hoshino H1, Obata H2, Saito S3.
Abstract
Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.
Translation -Cymbalta increases seratonin and noradrenaline levels in the spinal cord and reduces associated spinal pain.
Document #8
https://www.ncbi.nlm...pubmed/25154730
Eur J Pain. 2015 May;19(5):649-60. doi: 10.1002/ejp.586. Epub 2014 Aug 25.
A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.
Chu KL1, Xu J, Frost J, Li L, Gomez E, Dart MJ, Jarvis MF, Meyer MD, McGaraughty S.
Abstract
The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50 = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception.
METHODS: Systemic administration of A-1262543 (1-10 mg/kg, intraperitoneal) dose-dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex (mPFC) were examined after injection of 3 mg/kg of A-1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor.
RESULTS: Systemic administration of A-1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive-specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A-1262543 and duloxetine reduced the evoked and spontaneous firing of 'pain-responsive' (PR) neurones in the mPFC. Duloxetine, but not A-1262543, also inhibited the firing of pain non-responsive (nPR) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non-pain endpoints.
CONCLUSIONS: These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, in particular, dampening the firing of PR neurones in the mPFC.
Translation - Cymbalta does not effect the pain sensing nerves in the spinal cord but does reduce the activity of the nerves bringing signals back up to the prefrontal cortex and thus reducing the perception of pain.
Document #9
https://www.ncbi.nlm...les/PMC3171868/
Br J Pharmacol. 2011 Sep; 164(1): 159–169.
A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy
T Mixcoatl-Zecuatl and CG Jolivalt
These results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain.
Translation - Cymbalta seratonin receptor control helps control pain in peripheral (around the outside) nerves.
Document #10
https://www.ncbi.nlm...pubmed/24933334
Pharmacol Biochem Behav. 2014 Sep;124:238-44. doi: 10.1016/j.pbb.2014.06.005. Epub 2014 Jun 14.
Augmentation of antidepressant effects of duloxetine and bupropion by caffeine in mice.
Kale PP1, Addepalli V2.
Abstract
There is an unmet need in the treatment of depression suggesting requirement of new therapeutic approaches having better efficacy and safety profile. Patients receiving antidepressant therapy generally consume caffeine in the form of tea or coffee. The objective of the present study was to evaluate the augmentation of antidepressant effects of duloxetine and/or bupropion with caffeine. Male Swiss Albino mice received treatment of normal saline (10 ml/kg), 'caffeine alone' (10mg/kg), 'duloxetine alone' (10mg/kg), 'bupropion alone' (10mg/kg), caffeine+duloxetine (5mg/kg, each), bupropion+caffeine (5mg/kg, each), and bupropion+duloxetine (5mg/kg, each) through the intra-peritoneal route. The immobility period was analyzed 30 min after the treatment in forced swim and tail suspension tests. Norepinephrine, dopamine, and serotonin levels were analyzed in hippocampus, cerebral cortex and whole brain using HPLC with fluorescence detector. Euthanasia was performed 1h after treatment. Comparison between vehicle treated group and other groups showed significant decrease in immobility in all drug treated groups in both antidepressant models. Caffeine plus duloxetine treated group was better among the combination treated groups in terms of decrease in immobility and increase in norepinephrine, dopamine, and serotonin levels in hippocampi, cerebral cortices, and whole brain when compared to their respective monotherapy treated groups. These combination approaches may help in reducing the dose of duloxetine/bupropion, and consequently lower the associated side/adverse effects.
Translation - Caffiene in combination with Cymbalta helps decrease fatique and sluggishness (side effects of Cymbalta). It also increased concentrations of norepinephrine, dopamine and seratonin in the hippocampus, cerebral cortex and the whole brain.
Document #11
https://www.ncbi.nlm...pubmed/23522402
J Psychiatr Res. 2013 Jun;47(6):802-8. doi: 10.1016/j.jpsychires.2013.02.013. Epub 2013 Mar 19.
Chronic administration of duloxetine and mirtazapine downregulates proapoptotic proteins and upregulates neurotrophin gene expression in the hippocampus and cerebral cortex of mice.
Engel D1, Zomkowski AD, Lieberknecht V, Rodrigues AL, Gabilan NH.
Abstract
Structural alterations in the limbic system, neuronal cell loss, and low levels of neurotrophins have been implicated in the pathogenesis of depression. While it is generally accepted that increasing monoamine levels in the brain can effectively alleviate depression, the precise neurobiological mechanisms involved are unclear. In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic (natural cell deatah) and neurotrophic proteins (promotes growth, survival and specialize) in the cerebral cortex and hippocampus of mice. Duloxetine (10 mg/kg) and mirtazapine (3 mg/kg) were chronically administered for 21 days, and qRT-PCR analysis was carried for the following: neurotrophins (BDNF, NGF, FGF-2, and NT-3); anti-apoptotic proteins (Bcl-2 and Bcl-xL) and pro-apoptotic proteins (Bax, Bad, and p53). Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex. Mirtazapine decreased Bcl-xL and Bax expression in the hippocampus, and Bad and p53 expression in both the hippocampus and cerebral cortex. Mirtazapine also increased the expression of neurotrophins, NGF and NT-3, in the cerebral cortex. These results suggest that duloxetine and mirtazapine could elicit their therapeutic effect by modulating the activity of apoptotic and neurotrophic pathways, thus enhancing plasticity and cell survival in depressive patients.
Translation - Cymbalta increased production of BDNF (brain-derived neurotrophic factor). BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate. Cymbalta increases the production of one protein for apotosis (cell death), 2 for cell growth and survival and one cell membrane protein in the cerebral cortex. In addition it increases the protein for cell membranes in the hippocampus. Cymbalta decreases a protein antigen used to fight cellular tumors and 2 proteins used to promote cell death.
Document #12
https://www.ncbi.nlm...pubmed/23010381
Pharmacol Biochem Behav. 2012 Dec;103(2):408-17. doi: 10.1016/j.pbb.2012.09.011. Epub 2012 Sep 23.
The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test.
Zomkowski AD1, Engel D, Cunha MP, Gabilan NH, Rodrigues AL.
Abstract
Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine-NO-cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1-30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1-30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine-NO-cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents.
Translation - Cymbalta reduces nitrous oxide levels in the hippocampua and cerebral cortex. Since it was first identified to play an important role in relaxation of blood vessels, nitric oxide has been demonstrated to regulate many biological processes, especially in the central nervous system. Of the three types of enzymes that produce nitric oxide in humans and rodents, neuronal type is found almost exclusively in the nervous system. This gaseous molecule is a nonclassical neurotransmitter, which maintains the activities of neural cells and regulates the normal functions of brain. It appears to play a role in promoting the transfer of nerve signals from one neuron to another, maintaining the synaptic strength. Meanwhile, nitric oxide is a unique regulator on neurogenesis (new nerve cell production) and synaptogenesis, producing the positive or negative effects upon different signal pathways or cellular origins and locations. Based on its significant roles in neural plasticity, nitric oxide is involved in a number of central nervous diseases, such as ischemia, depression, anxiety, and Alzheimer's disease.
Document #13
https://www.ncbi.nlm...pubmed/21820879
Psychiatry Res. 2011 Nov 30;194(2):157-62. doi: 10.1016/j.pscychresns.2011.03.011. Epub 2011 Aug 6.
Duloxetine's modest short-term influences in subcortical structures of first episode drug-naïve patients with major depressive disorder and panic disorder.
Lai CH1, Wu YT.
Abstract
We developed this study to follow up the hanges in subcortical structures after 6 weeks' treatment with therapy of duloxetine in first episode drug-naïve patients with major depressive disorder and panic disorder. Fifteen patients received duloxetine 60mg/d therapy for 6 weeks and achieved remission. They all underwent structural magnetic resonance imaging (MRI) of the brain at baseline and week 6. Fifteen healthy controls were also scanned twice at baseline and week 6 to exclude possible biases. Structural MRI data were preprocessed with FMRIB's Integrated Registration and Segmentation Tool function (FIRST version 1.2) of FSL (FMRIB Software Library; version 4.1.1) to perform subcortical segmentations of the brain using a shape and appearance model. Nonparametric corrections of these structural volumes in an F-test between pre- and post-treatment were used to identify the changes after duloxetine therapy. A false discovery correction of the F-test by FIRST was also performed. A paired t-test using SPSS was applied to confirm the changes in these structures. The patients had consistent changes of volumes in bilateral nucleus accumbens, left putamen, left hippocampus and brainstem after 6 weeks of treatment with duloxetine. There were no consistent changes in other subcortical structures. There were modest increases of the volumes of the above areas, which were not significant after false discovery correction by FIRST F-test comparisons. The volumetric increases were correlated with responses of clinical symptoms. The results suggested that duloxetine possibly contributed to modest increases in several subcortical areas of these patients with remission.
Translation - Consistent changes of volumes in bilateral nucleus accumbens, a region of the forebrain, (As a whole, the nucleus accumbens has a significant role in the cognitive processing of aversion, motivation, pleasure, reward and reinforcement learning; hence, it has a significant role in addiction. It plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect. It is involved in the encoding of new motor programs as well.), left putamen (located at the base of the forebrain it's main function is to regulate movements and influence various types of learning. It employs GABA, acetylcholine, and enkephalin to perform its functions. The putamen also plays a role in degenerative neurological disorders, such as Parkinson's disease.), left hippocampus and brainstem after 6 weeks of treatment with duloxetine.
Document #14
https://www.ncbi.nlm...pubmed/20381469
Brain Res. 2010 Jun 23;1341:93-9. doi: 10.1016/j.brainres.2010.03.086. Epub 2010 Apr 8.
Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice.
Marlatt MW1, Lucassen PJ, van Praag H.
Abstract
Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here, we assessed neurogenesis and open-field behavior in 2-month-old female C57Bl/6 mice after 28days of treatment with either fluoxetine (18mg/kg), duloxetine (2, 6 or 18mg/kg) or exercise. New cell survival, as measured by 5-bromo-2'-deoxyuridine (BrdU)-labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open-field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data show that the neurogenic response to exercise is much stronger than to antidepressants and imply a low likelihood that anxiolytic effects of these drugs are mediated by adult neurogenesis in C57Bl/6 mice.
Document #15
https://www.ncbi.nlm...pubmed/20159945
Mol Pharmacol. 2010 May;77(5):846-53. doi: 10.1124/mol.109.063081. Epub 2010 Feb 16.
Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms.
Calabrese F1, Molteni R, Cattaneo A, Macchi F, Racagni G, Gennarelli M, Ellenbroek BA, Riva MA.
Abstract
Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.
Translation - Cymbalta returns BDNF to proper levels and a return of neural plasticity (the ability of the brain to change and develop through it's life).
Document #16
https://www.ncbi.nlm...pubmed/18751896
Neurochem Res. 2009 Mar;34(3):542-55. doi: 10.1007/s11064-008-9818-2. Epub 2008 Aug 27.
Brain region-specific effects of short-term treatment with duloxetine, venlafaxine, milnacipran and sertraline on monoamine metabolism in rats.
Muneoka K1, Shirayama Y, Takigawa M, Shioda S.
Abstract
We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.
Translation - Cymbalta initially increased seratonin in the brain stem, reduced reuptake (reuse) in the hippocampus, hypothalmus and frontal cortex. Also, Cymbalta icreased dopamine levels and decreased reuptake of dopamine in the nucleus accumbens and the substantia nigra(plays an important role in reward and movement). It also caused small increases in noradrenaline.
Document #17
https://www.ncbi.nlm...pubmed/17327885
Neuropsychopharmacology. 2007 Nov;32(11):2351-9. Epub 2007 Feb 28.
Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein.
Calabrese F1, Molteni R, Maj PF, Cattaneo A, Gennarelli M, Racagni G, Riva MA.
Abstract
There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.
Translation - Chronic treatment with Cymbalta not only produces a marked increase in the function of the BDNF mRNA but also the manufacturing of BDNF itself, and may also affect the subcellular redistribution of BDNF).
Document #18
https://www.ncbi.nlm.../pubmed/9686935
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):600-10.
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
Rueter LE1, Kasamo K, de Montigny C, Blier P.
Abstract
Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - Demonstrated the blocking of seratonin reuptake by Cymbalta. It also increased seratonin levels in the hippocampus. Although seratonin reuptake was blocked in the frontal cortex seratonin levels remained constant. Chronic use (21 days is chronic?) showed increase release of noradrenaline in the hippocampus and frontal cortex.
Document #19
https://www.ncbi.nlm.../pubmed/9580577
J Pharmacol Exp Ther. 1998 May;285(2):404-12.
Electrophysiological characterization of the effect of long-term duloxetine administration on the rat serotonergic and noradrenergic systems.
Rueter LE1, De Montigny C, Blier P.
Abstract
Duloxetine is a dual serotonin (5-HT)/norepinephrine (NE) re-uptake blocker with antidepressant potential. In the present in vivo electrophysiological study, the changes in the function of the rat 5-HT and NE systems after 2- and 21-day administration of duloxetine (20 mg/kg/day) were assessed in the dorsal hippocampus and the dorsal raphe nucleus (DRN). The firing rate of DRN neurons was decreased after 2 days of duloxetine, but returned to the control level after 21-day administration. This recovery of firing rate was presumably due to the desensitization of the DRN somatodendritic 5-HT1A autoreceptors found after long-term duloxetine administration. Overall serotonergic tone was assessed by examining the ability of the 5-HT1A antagonist WAY 100635 to alter hippocampal firing. WAY 100635 increased hippocampal firing rates in 21-day treated rats to a greater extent than in 2-day treated or control rats, suggesting that long-term administration induced an increase in endogenous levels of 5-HT in postsynaptic regions. This increase in 5-HT levels was accompanied by selective changes in the 5-HT and NE systems induced by long-term duloxetine administration, i.e., the desensitization of the alpha-2 adrenergic heteroreceptor on 5-HT terminals and the continued blockade of the 5-HT transporters. In contrast, the sensitivity of the alpha-2 adrenergic and terminal 5-HT1B autoreceptors, as well as that of the postsynaptic 5-HT1A receptor after 21-day treatment was unchanged. Therefore, this study demonstrates that duloxetine increases serotonergic tone in a limbic forebrain structure and may therefore be effective in the treatment of depression.
Translation - Cymbalta initially increased the firing of nerve cells in the dorsal raphe nucleus (The dorsal raphe nucleus is located on the midline of the brainstem The dorsal raphe nucleus have long been implicated in depression. Some studies have suggested that the dorsal raphe may be decreased in size in people with depression and, paradoxically, an increased cell density in those who commit suicide.) but firing rates returned to normal after 21 days due to fatique in the seratonin receptors. It also increased seratonin in the forebrain.
Document #20
https://www.ncbi.nlm.../pubmed/9105878
Eur J Pharmacol. 1997 Mar 26;323(1):69-73.
Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.
Smith JE1, Lakoski JM.
Abstract
The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing. When duloxetine was co-applied with 5-HT, the recovery response (RT50 values) of hippocampal pyramidal neurons to 5-HT application was not altered. In contrast, co-application of fluoxetine with 5-HT at the same iontophoretic currents significantly increased (59%) the RT50 values produced by 5-HT application alone. This physiological and pharmacological study contributes to understanding the cellular mechanisms of these agents which may be useful in the treatment of depression.
Translation - Cymbalta inhibited dorsal raphe nucleus cell firing. In the hippocampus little decrease was noted in cell firing.
Document #21
https://www.ncbi.nlm.../pubmed/8613930
J Pharmacol Exp Ther. 1996 Apr;277(1):278-86.
Blockade of the serotonin and norepinephrine uptake processes by duloxetine: in vitro and in vivo studies in the rat brain.
Kasamo K1, Blier P, De Montigny C.
Abstract
In in vitro uptake experiments, duloxetine inhibited [3H]5-hydroxytryptamine (5-HT) and [3H]norepinephrine (NE) uptake in hippocampus slices of control rats with IC50 values of 28 and 46 nM, respectively. The uptake of both[3H]5-HT and [3H]NE was equipotently inhibited in hippocampus slices prepared from rats treated for 2 days with different doses of duloxetine (5, 10, 15 and 20 mg/kg/day s.c.). In in vivo electrophysiological experiments in the hippocampus, the effects of duloxetine on the suppression of CA3 pyramidal neuronal firing activity by microiontophoretically applied 5-HT and NE were examined with two modes of administration. Five successive i.v. injections (2 mg/kg each) significantly and dose-dependently prolonged the recovery time of the firing activity of hippocampus CA3 pyramidal neurons from the 5-HT applications. A 2-day treatment (10, 15 and 20 mg/kg/day s.c.) also increased the recovery time in a dose-dependent manner. Whereas the recovery time from NE applications was unaffected by low doses of duloxetine (2 mg/kg i.v.; 10 mg/kg/day for 2 days), it was prolonged significantly by higher doses (8 and 1 0 mg/kg iv.; 20 mg/kg/day for 2 days). Acute i.v. injections of duloxetine suppressed the spontaneous firing activity of dorsal raphe 5-HT and locus ceruleus NE neurons with ED50 values of 99 and 475 microgram/kg, respectively. Taken together, the present results confirmed that duloxetine is a dual 5-HT/NE uptake inhibitor. Furthermore, the results obtained in in vivo experiments indicate that duloxetine has a preferential inhibitory effect on the 5-HT transporter.
Translation - Cymbalta inhibited the reuptake of both seratonin and noradrenaline in the hippocampus. It inhibited seratonin reuptake more than noradrenaline.
Document #22
https://www.ncbi.nlm...les/PMC3413810/
J Mol Neurosci. 2012 Sep; 48(1): 167–175.
Differential BDNF Responses of Triple Versus Dual Reuptake Inhibition in Neuronal and Astrocytoma Cells as well as in Rat Hippocampus and Prefrontal Cortex
,1,2,3 Gunter Kenis,1,2 Maria S. Quinton,3 Sharon Engel,3 Larry Melnick,3 and Rudy Schreiber3,4
Abstract
Monoamine reuptake inhibitors increase brain-derived neurotrophic factor (BDNF) activity, and this growth factor is regarded as an interesting target for developing new antidepressant drugs. The aims of this study were to evaluate whether monoaminergic reuptake inhibition increases BDNF in vivo and in vitro as predicted by the neurotrophic hypothesis of depression, and whether triple reuptake inhibition has a superior BDNF response compared to dual reuptake inhibition. Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. The prefrontal cortex contained increased BDNF levels only after DOV 216,303 treatment. In vitro, neither duloxetine nor DOV 216,303 altered intracellular BDNF levels in murine HT22 neuronal cells. In contrast, BDNF release was more effectively decreased following treatment with DOV 216,303 in these cells. In rat C62B astrocytomas, both antidepressants increased intracellular BDNF levels at their highest nontoxic concentration. C62B astrocytomas did not release BDNF, even after antidepressant treatment. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell–cell interactions, and different mechanisms of action of antidepressants used.
Translation - Cymbalta returned BDNF levels to normal in the hippocampus within 21 days.
Document #23
https://www.ncbi.nlm...les/PMC3176563/
Neuropsychopharmacology. 2011 Oct; 36(11): 2266–2275.
Short-Term Duloxetine Administration Affects Neural Correlates of Mood-Congruent Memory
Indira Tendolkar,1,2,3,* Guido van Wingen,1,4,5 Maren Urner,1,6 Robbert Jan Verkes,2 and Guillén Fernández1,4
Abstract
It is unknown how antidepressants reverse mood-congruent memory bias, a cognitive core factor causing and maintaining depression. Using a double-blind, placebo-controlled, cross-over design, we investigated the effect of a short-term treatment (14 days) with the dual reuptake inhibitor duloxetine on neural correlates of mood-congruent and mood-incongruent memory formation and retrieval in healthy volunteers who underwent a sad mood induction procedure. Duloxetine did not affect acute mood state or memory performance, but interacted with brain processes mediating mood-congruent memory. It decreased activity related to successful memory formation for mood-congruent and -incongruent items in a set of brain regions comprising the putamen and the middle frontal gyrus, as well as the middle and the anterior cingulate cortex. Duloxetine specifically increased amygdala activity related to successful memory retrieval for mood-incongruent items. Here we show that short-term administration of duloxetine affects the neural correlates of emotional memory formation and retrieval in a set of brain regions whose processing is related to affective state and its regulation. While duloxetine suppressed the neural correlates of emotional memory formation in general, it specifically enhanced amygdala processes associated with mood-incongruent memory retrieval. This pattern of results shows how an antidepressant may reduce emotional memory formation and reverse mood-congruent processing biases at retrieval.
Translation - A 14 day treatment with Cymbalta decreased activities related to memory formation in the putamen, frontal gyrus and anterior cingulate cortex. On the other hand it increased memory retrieval in the amygdala.
Document #24
https://www.ncbi.nlm...les/PMC4713700/
Int J Clin Exp Pathol. 2015; 8(11): 15454–15461.
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
Bing Pan,1,* Yamei Liu2,*
Abstract
Depression is a major mood disorder affecting people worldwide. The posttranscriptional gene regulation mediated by microRNAs (miRNAs) which may have critical roles in the pathogenesis of depression. However, to date, little is known about the effects of the antidepressant drug duloxetine on miRNA expression profile in chronic unpredictable mild stress (CUMS)-induced depression model in mice. Healthy adult male Kunming mice were randomly divided into three groups: control group, model group and duloxetine group. Sucrose preference test and open field test were used to represent the behavioral change. MiRNAs levels in frontal lobe and hippocampus of mice were analyzed using miRNA microarrays assay. We observed that long-term treatment with duloxetine significantly ameliorated the CUMS procedure-induced sucrose preference decreases and mice treated with duloxetine demonstrated a reversal of the number of crossings, and rearings reduced by CUMS. A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
Translation- Cymbalta increased the activity of two miRNA in the hippocampus (miRNA-132 which functions to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.; and miR-18a which triggers the function of other RNA) and decreases the function of two other miRNA (miR-134 is a brain-specific microRNA localised in hippocampal neurons and indirectly regulate synaptic development and is thought to mediate Creb protein giving it a role in higher brain functions such a memory formation; and miR-124a which has been found to be the most abundant microRNA expressed in nerve cells. It can change the structure of Glutamate receptors in the prefrontal cortex.)
Document #25
https://www.ncbi.nlm...les/PMC3055320/
Neuropsychopharmacology. 2010 Oct; 35(11): 2305–2317.
Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder
Marina López-Solà,1,2 Jesus Pujol,1,3,* Rosa Hernández-Ribas,1,4,5 Ben J Harrison,1,6 Oren Contreras-Rodríguez,1,7 Carles Soriano-Mas,1,7 Joan Deus,1,8 Héctor Ortiz,1 José M Menchón,4,5 Julio Vallejo,2,5 and Narcís Cardoner1,4,5
Abstract
Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
Translation - Cymbalta reduced pain nerve signals in the pregenual anterior cingulate cortex (It plays a role in a wide variety of autonomic functions, such as regulating blood pressure and heart rate and is involved in certain higher-level functions, such as reward anticipation, decision-making, impulse control, and emotion.), right prefrontal cortex, and pons (The pons is part of the brainstem that conduct signals from the brain down to the cerebellum and medulla, and tracts that carry the sensory signals up into the thalamus.The pons contains nuclei that relay signals from the forebrain to the cerebellum, along with nuclei that deal primarily with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture.).
Document #26
https://www.ncbi.nlm...pubmed/25880400
2015 Apr 14;15:82. doi: 10.1186/s12888-015-0457-2.
Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine.
Fu CH1,2, Costafreda SG3,4, Sankar A5, Adams TM6, Rasenick MM7,8, Liu P9, Donati R10,11, Maglanoc LA12, Horton P13, Marangell LB14.
Abstract
Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI.
RESULTS: A significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response.
CONCLUSIONS: Baseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation.
Translation - Cymbalta normalized activation of the posterior cingulate. Imaging studies indicate a prominent role for the posterior cingulate cortex in pain and episodic memory retrieval. Increased size of posterior ventral cingulate cortex is related to working memory decline. The posterior cingulate cortex has been implicated as a key part of several control networks. The posterior cingulate cortex has also been firmly linked to prominent emotional experiences . Thus, it has been hypothesized that the emotional importance of personal memories may contribute to the strength and consistency of activity in the posterior cingulate cortex upon successful recollection of these memories. The posterior cingulate cortex is significantly activated by emotional stimuli.
Document #27
https://www.ncbi.nlm...pubmed/21195195
Neuroimage. 2011 Mar 15;55(2):825-31. doi: 10.1016/j.neuroimage.2010.12.051. Epub 2010 Dec 30.
Subchronic duloxetine administration alters the extended amygdala circuitry in healthy individuals.
van Marle HJ1, Tendolkar I, Urner M, Verkes RJ, Fernández G, van Wingen G.
Abstract
Neuroimaging studies have consistently linked depression to hyperactivation of a (para)limbic affective processing network centered around the amygdala. Recent studies have started to investigate how antidepressant drugs affect amygdala reactivity in healthy individuals, but the influence of their subchronic administration on the functional integrity of the affective neurocircuitry as a whole remains unknown. Therefore, we used functional magnetic resonance imaging in nineteen healthy volunteers to assess the effect of two weeks of administration of the combined serotonin and norepinephrine reuptake inhibitor duloxetine (60 mg) on reactivity and functional connectivity within the affective neurocircuitry in a double-blind, placebo-controlled, crossover design. Using an emotional face matching task we demonstrated that duloxetine reduced neural responses in affect processing regions including the amygdala, the anterior insula, the thalamus and the ventral aspect of the anterior cingulate cortex. Additionally, functional coupling between the amygdala and the anterior insula was enhanced by the drug. These results suggest that duloxetine attenuates the bottom-up processing of biologically salient information in an extended amygdala circuitry, while at the same time possibly potentiating the effective communication between its subparts. Since hyperactivation of the same affective neurocircuitry is thought to underlie emotional dysfunction in depression, these results suggest a putative neural mechanism through which duloxetine could normalize typical negativity biases in depression.
Translation - Cymbalta reduced nerve responses in the amygdala, anterior insula (The insulae are believed to be involved in consciousness and play a role in diverse functions usually linked to emotion or the regulation of the body's homeostasis. These functions include perception, motor control, self-awareness, cognitive functioning, and interpersonal experience. In relation to these, it is involved in psychopathology.), thalmus (Some of its functions are the relaying of sensory and motor signals to the cerebral cortex, and the regulation of consciousness, sleep, and alertness.) and cingulate cortex. Communication between the amygdala and the anterior insula were increased.
Document #28
https://www.ncbi.nlm...les/PMC3055320/
Neuropsychopharmacology. 2010 Oct; 35(11): 2305–2317.
Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder
Marina López-Solà,1,2 Jesus Pujol,1,3,* Rosa Hernández-Ribas,1,4,5 Ben J Harrison,1,6 Oren Contreras-Rodríguez,1,7 Carles Soriano-Mas,1,7 Joan Deus,1,8 Héctor Ortiz,1 José M Menchón,4,5 Julio Vallejo,2,5 and Narcís Cardoner1,4,5
Abstract
Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
Translation - Cymblta reducted pain perception the pregenual anterior cingulate cortex, right prefrontal cortex, and pons.
Document #29
https://www.ncbi.nlm...pubmed/23507186
Psychoneuroendocrinology. 2013 Sep;38(9):1824-8. doi: 10.1016/j.psyneuen.2013.02.009. Epub 2013 Mar 16.
NGF serum levels variations in major depressed patients receiving duloxetine.
Martino M1, Rocchi G, Escelsior A, Contini P, Colicchio S, de Berardis D, Amore M, Fornaro P, Fornaro M.
Abstract
Nerve growth factor (NGF) is involved in the modulation of the neuro-endocrine-immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI.
METHODS: 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively.
RESULTS: According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline.
CONCLUSIONS: A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders.
Translation - Nerve growth factor concentrations were lower in depressed patients. Cymbalta further lowered nerve growth factor concentrations.
Document #30
https://www.ncbi.nlm...pubmed/20305306
Neuropsychopharmacol Hung. 2010 Mar;12(1):301-7.
[The effects of duloxetine on beta-actin stress response in rat brain].
Szücs S1, Pákáski M, Domokos A, Kálmán J Jr, Kálmán S, Garab D, Penke B, Szabó G, Janka Z, Kálmán J.
Abstract
Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes. Wistar rats were exposed to immobilization stress for five hours daily through 21 days, while part of the animals received 45 mg/bwkg of duloxetine. At the end of the third week total RNA was purified from the cortex and hippocampus. The amount of beta-actin, APP and MAPK-1 mRNA was determined by real time PCR method. On protein level, semiquantitative measurement was performed by Western blot. The expression of beta-actin mRNA in the animals exposed to stress was four times as intense as in the control group. The increase in the beta-actin mRNA levels was repressed by the duloxetine treatment. In the case of APP and MAPK-1 no changes were detected. According to the Western blot results, the antidepressant treatment slightly, the drug along with the stress treatment strongly decreased the amount of the beta-actin protein. Our findings indicate that antidepressant treatment with duloxetine could play a protective role against the chronic stress-induced changes in the nervous system, such as disorders of synaptic plasticity, and the consequent cognitive dysfunctions in case of both affective disorders and AD.
Translation- Stress increases activity of the beta-actin mRNA (major part of muscle contractions) and Cymbalta decreased the activity of the beta-actin mRNA
Document #31
https://www.ncbi.nlm...pubmed/19020498
Neuropsychopharmacology. 2009 May;34(6):1523-32. doi: 10.1038/npp.2008.208. Epub 2008 Nov 19.
Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine.
Molteni R1, Calabrese F, Cattaneo A, Mancini M, Gennarelli M, Racagni G, Riva MA.
Abstract
Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.
Translation - Stress increases BDNF concentration but Cymbalta treatment decreased the concentration. Pretreatment with Cymbalta had the opposite effect.
Document #32
https://www.ncbi.nlm...pubmed/18704370
Psychopharmacology (Berl). 2008 Dec;201(2):285-92. doi: 10.1007/s00213-008-1276-7. Epub 2008 Aug 14.
Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment.
Molteni R1, Calabrese F, Mancini M, Racagni G, Riva MA.
Abstract
RATIONALE: Therapeutic efficacy of antidepressant drugs appears to be related to their ability in producing neuroadaptive changes that restore normal brain function. Activity-regulated cytoskeletal associated protein (Arc) is an effector immediate early gene that plays a fundamental role in activity-dependent neural plasticity in corticolimbic brain regions and has been implicated in the modulation of several functions known to be profoundly perturbed in depressive states.
OBJECTIVE: In the present study, we investigated transcriptional and translational changes of Arc in response to acute or chronic treatment with the novel antidepressant duloxetine.
RESULTS: Although a limited increase of Arc messenger RNA (mRNA) levels was found in some structures after acute antidepressant administration, a marked up-regulation of its gene expression was found after chronic treatment, primarily at the level of frontal cortex. The changes observed after prolonged duloxetine administration strongly correlates with those previously reported on brain-derived neurotrophic factor mRNA levels Calabrese et al. In addition, we found an anatomical-specific influence of chronic duloxetine on stress-dependent Arc modulation, which was limited to the frontal cortex.
CONCLUSIONS: We suggest that these neuroadaptive changes, among others, might contribute to the normalization of neuroplastic defects associated with mood disorders.
Translation - Chronic use of Cymbalta increases Arc concentrations in the frontal cortex (Arc is widely considered to be an important protein in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunctions in the production of Arc protein has been implicated as an important factor in understanding of various neurological conditions including: Amnesia; Alzheimer's disease; Autism spectrum disorders; and, Fragile X syndrome)
Misc.
http://www.ncbi.nlm....pubmed/23732229
With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning
http://www.ncbi.nlm....pubmed/23675317
We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining
https://www.ncbi.nlm...pubmed/23400819
Overall, the results suggest that citalopram at the recommended human doses induces some genetic alterations, which can adversely affect the normal cellular functioning in mice. The mechanism(s) by which citalopram cause this adverse effect appear related, in part, to primary DNA strand breakage as detected by the comet assay as well as clastogenic and aneugenic events as detected by the FISH assay. Therefore, the clinical use of citalopram must be weighed against the risks of genetic damages in citalopram users.
https://www.ncbi.nlm...pubmed/23280034
The results showed that the drug fluoxetine was SCE and sperm abnormalities inducer. The response of this compound was dose-dependent, and showed that the highest tested dose increased about two times SCE and four times the sperm abnormalities control level. The cellular proliferation kinetics was not affected by the chemical, and the mitotic indexes were slightly diminished with the highest dose. The percentage of sperm count and sperm motility decreased (p < 0.01) with increased the dose of treatment.
https://www.ncbi.nlm...pubmed/23232079
Overall, this study provides that citalopram at the recommended human doses after long-term treatment is genotoxic for mouse germ cells (DNA breaks). Thus, male patients receiving citalopram may stand at higher risk for abnormal reproductive outcomes, particularly in the reproductive ages.
https://www.ncbi.nlm...pubmed/22750076
Genetic changes occurring in somatic cells of the wing's imaginal discs, cause the formation of mutant clones on the wing blade. The results of this study show that citalopram had a genotoxic effect in the Drosophila SMART. Sertraline, however, did not show any genotoxic effect in balancer heterozygous wings. This study concluded that more information is needed to be certain regarding the mutagenic effects of sertraline.
https://www.ncbi.nlm...pubmed/21937534
Olanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs and are commonly used for the treatments of schizophrenia and bipolar disorders.However, the application of the highest drug concentrations (250 mg/L and above) caused the sterility in lymphocyte cultures. It is concluded that the tested three different atypical antipsychotic drugs can be used safely, but it is necessary to consider the cytotoxic effects that are likely to appear depending on the doses exposed.
https://www.ncbi.nlm...pubmed/20542924
Our results indicated that the tested antipsychotic drug did not induce SCEs in lymphocytes of treated cultures. However, the application of the highest OLZ concentration caused oxidative stress. It is concluded that the OLZ can be used safely, but it is necessary to consider the tissue damages that are likely to appear depending on the oxidative stress.
https://www.ncbi.nlm...pubmed/18804223
Patients treated with selective serotonin reuptake inhibitors had a mean of 8.1% +/- 5.4% normal forms per ejaculate. A significant increase in the amount of denatured single strand DNA in total cellular DNA was found in patients treated with selective serotonin reuptake inhibitors compared with that in controls (43.2% +/- 11.4% vs 21.4% +/- 10.6%, p = 0.01). Each semen analysis parameter significantly correlated with treatment duration.
https://www.ncbi.nlm...pubmed/12904104
Classical antidepressants such as monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants (TCAs) seem to have the highest potential to induce liver damage compared with the newer drugs such as selective serotonin re-uptake inhibitors (SSRIs). The potential for severe hepatotoxicity associated with nefazodone is stressed. Guidelines for therapy and prevention of antidepressant-induced hepatotoxicity are also discussed.
https://www.ncbi.nlm...pubmed/11482523
The effects of acute (24 h) exposure to the antidepressants amitriptyline, imipramine (both tricyclics), fluoxetine (a selective serotonin re-uptake inhibitor) and tranylcypromine (a monoamine oxidase inhibitor) on DNA damage in cultured C6 rat glioma cells were determined using an alkaline comet assay. The data show that the antidepressants induce significant amounts DNA damage in C6 cells
https://www.ncbi.nlm...pubmed/20851831
The recombinogenic potential of this antidepressant in A. nidulans may be associated with the recombinational repair of citalopram-induced DNA strand breaks
https://www.ncbi.nlm...pubmed/15036127
Patients with both generalized anxiety disorder and major depression exposed to daily doses of sertraline do not indicate a possible clastogenic hazard.
https://www.ncbi.nlm...les/PMC3702119/
We conclude that although, Wellbutrin exerts potential genotoxic effects in cultured lymphocytes, its cytogenetic effects are very unlikely to occur in blood cultures of WB-administered subjects.
https://www.ncbi.nlm...pubmed/16751836
Neurotoxic reaction to citalopram.
Summary
Cymbalta
⦁ causes weight gain
⦁ causes liver damage
⦁ slows clotting
⦁ damages red blood cells beginning in 2 weeks and is cumulative
⦁ does not damage DNA
⦁ controls/alters RNA and miRNA performamce resulting in different effects than the DNA genes are coded for
⦁ alters BDNF mRNA but also the manufacturing of BDNF (brain-derived neurotrophic factor) itself. Thus RNA and BDNF controls nerve cell production and survival
⦁ returns the glutamate gene function to normal activity in the hippocampus. Glutamate is an amino acid, one of the twenty amino acids used to construct proteins, and as a consequence is found in high concentration in every part of the body. In the nervous system it plays a special additional role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. In fact glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It is no wonder that Cymbalta can cause such varied side effects and withdrawal symptoms as it can potentially effect all nerve cells in the brain and nervous system.
⦁ increases seratonin and noradrenaline levels in the spinal cord
⦁ has great effect on nerve cell growth, survival and death.
⦁ effects nitrous oxide levels in the brain.
⦁ decreases reuptake of dopamine
⦁ increases memory retrieval in the amygdala. (fear center in the brain)
⦁ effects the pons that relay signals from the forebrain to the cerebellum, along with nuclei that deal primarily with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture.).
⦁ lowers nerve growth factor concentrations
⦁ decreased the activity of the beta-actin mRNA Beta actin is used in muscle contractions.
http://www.cymbaltaw...elps#entry66904
Details and research on Cymbalta damage and effects.
AM - In extremely acidic conditions, or when a person's stomach contents move out of the stomach slowly, Cymbalta, unprotected by the enteric coating may undergo hydrolysis to form Naphthol. Caution is advised in using Cymbalta in patients with conditions thatmay slow gastric emptying." "Naphthol is found in pesticides and is toxic to lungs and mucous membranes. Repeated exposure to Naphthol may produce general deterioration of health by an accumulation in one or many human organs." "Naphthol may cause DNA damage to human lymphocytes."
https://dailymed.nlm...f2-c185fbad64ba
"In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). "
http://www.cymbaltaw...age/?hl=caution
Damage caused by Cymbalta and other antidepressants.
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Cymbalta and Alcohol
http://www.fda.gov/d...y/ucm088579.pdf
Page 5 of 6 from FDA
Use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. Avoid heavy alcohol use while taking Cymbalta.
The FDA site says that 0.46% of Cymbalta users reported increased alcohol consumption.
https://www.ncbi.nlm...pubmed/25161814
Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.
Cymbalta lowers alcohol consumption.
https://www.ncbi.nlm...pubmed/18195589
Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats.
Decreased binge drinking in rats.
Note. The decrease in alcohol consumption would most likely not pertain to those suffering with mania and that is supported by looking at the alcohol related postings on this site where many report excessive consumption while being on Cymbalta.
Clonidine/Alcoholism
1) Clonidines effect on Alcohol consumption.
https://www.ncbi.nlm...pubmed/25085719
Alcohol. 2014 Sep;48(6):543-9. doi: 10.1016/j.alcohol.2014.07.002. Epub 2014 Jul 14.
The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.
Clonidine significantly reduced alcohol intake.
https://www.ncbi.nlm...pubmed/15551068
Psychopharmacology (Berl). 2005 May;179(2):366-73. Epub 2004 Nov 17.
Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats.
To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.
2) Clonidines effectiveness in treating alcohol withdrawal.
https://www.ncbi.nlm.../pubmed/3327372
Clonidine and alcohol withdrawal.
The alpha-2-adrenergic agonists in alcohol treatment seemed modestly effective for treatment of some parts of alcohol withdrawal.
https://www.ncbi.nlm.../pubmed/1969792
Drug Alcohol Depend. 1990 Feb;25(1):43-8.
The effect of clonidine and related substances on voluntary ethanol consumption in rats.
Clonidine, guanfacine and tiamenidine, in equihypotensive doses, significantly reduced alcohol intake in ethanol-preferring rats having free choice between 10% ethanol and drinking water. Water intake was only slightly reduced, especially during the first hours following the administration of clonidine. Simultaneous treatment with yohimbine attenuated the clonidine-induced reduction in ethanol intake. Putative central mechanisms underlying the observed inhibitory actions of clonidine and other alpha-2 adrenoceptor agonists on oral self-administration of alcohol are discussed.
https://www.ncbi.nlm...pubmed/21521867
https://www.ncbi.nlm.../pubmed/1103576
https://www.ncbi.nlm.../pubmed/7978098
https://www.ncbi.nlm.../pubmed/2646983
https://www.ncbi.nlm...pubmed/11091026
https://www.ncbi.nlm.../pubmed/6415735
https://www.ncbi.nlm.../pubmed/3300587
https://www.ncbi.nlm.../pubmed/3893195
https://www.ncbi.nlm.../pubmed/3441163
https://www.ncbi.nlm...pubmed/15551068
And many many more....
Hydroxyzine/alcoholism
There is no data on the use of hydroxyzine to reduce the desire/use of alcohol.
It has to be shown to not be effective in alcohol withdrawal.
Note - Neither clonidine nor hydroxyzine should be used WITH alcohol as it may cause a serious drop in blood pressure.
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Cymbalta and hyperglycemia
http://www.ehealthme...a/hyperglycemia
FDA and others number of reported cases of hyperglycemia
http://dailymed.nlm....F2-C185FBAD64BA
From NIH, a branch of the government.
http://www.ncbi.nlm....les/PMC3056054/
Research article on hyperglycemia.
http://www.accessdat...1427s030lbl.pdf
FDA reports of hyperglycemia.
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Mania/Sexual effects while taking Cymbalta.
Please note that many of these articles relate the high risk of mania as being related to bipolar disorder rather than Major Depression or Anxiety.
https://www.ncbi.nlm...pubmed/22024021
Persistent genital arousal disorder: successful treatment with duloxetine and pregabalin in two cases.
In both women, the treatment proved to be very successful over a long period of time. One of them experienced full remission (duloxetine) and the other one experienced substantial improvement (pregabalin), over a period now lasting for more than a year.
https://www.ncbi.nlm...pubmed/21091877
Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.
Cymbalta can cause sexual dysfunction (decreased sexual labido and performance).
https://www.ncbi.nlm...pubmed/17627739
Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder.
Same as above.
https://www.ncbi.nlm...pubmed/26003261
Psychiatric disorders and sexual dysfunction.
Same as above
https://dailymed.nlm...f2-c185fbad64ba
The following is from the drug insert information that come with Cymbalta.
5.8 Activation of Mania/Hypomania
In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients with a history of mania.
Note - Mania is a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together with lability of affect." Symptoms include ...
⦁ Inflated self-esteem or grandiosity
⦁ Decreased need for sleep (e.g., feels rested after 3 hours of sleep.)
⦁ More talkative than usual or pressure to keep talking.
⦁ Flights of ideas or subjective experience that thoughts are racing. Increase in goal directed activity, or psychomotor acceleration.
⦁ Distractibility (too easily drawn to unimportant or irrelevant external stimuli).
⦁ Excessive involvement in activities with a high likelihood of painful consequences.(e.g., extravagant shopping, sexual adventures or improbable commercial schemes). Wiki
6.6 Effects on Male and Female Sexual Function in Adults
Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials patients treated with CYMBALTA experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with CYMBALTA experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on CYMBALTA than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
http://www.gjpsy.uni...cle-mustafa.pdf
A Case of Possible Duloxetine-Induced Mania
"Her mood initially improved but two weeks into treatment she developed insomnia, hyperactivity and sexual arousal."
"Around the time of admission her symptoms constituted irritability, psychomotor agitation, pressure of speech, flight of ideas, insomnia, auditory and visual hallucinations, grandiose and persecutory delusions, aggressive and reckless behaviour, sexual disinhibition and lack of insight."
https://www.nami.org...tine-(Cymbalta)
The following is from the Nami data sheet on Cymbalta.
"Depression is also a part of bipolar illness. People with bipolar disorder who take antidepressants may be at risk for "switching" from depression into mania. Symptoms of mania include "high" or irritable mood, very high self esteem, decreased need for sleep, pressure to keep talking, racing thoughts, being easily distracted, frequently involved in activities with a large risk for bad consequences (for example, excessive buying sprees)."
http://www.mayoclini...ns/DRG-20067247
Some people may have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. If you or your caregiver notice any of these unwanted effects, tell your doctor right away.
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Cymbalta and the Liver
https://dailymed.nlm...185fbad64ba#s23
Drug insert for Cymbalta
Section - 5.2 Hepatotoxicity (Liver toxicity)
"These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury."
"In most patients, the median time to detection of the transaminase elevation was about two months."
Note - More details on liver issues at this site.
https://www.ncbi.nlm...les/PMC3773985/
"All 6 patients recovered without liver transplantation even though 3 had pre-existing chronic liver disease."
"Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury."
https://www.ncbi.nlm...ubmed/17257478/
'In a pooled analysis of 17,615 subjects, the incidence of serum alanine aminotransferase (ALT) levels > 3 times the upper limit of normal (ULN), > 5 ULN, and > 10 ULN were 1%, 0.5%, and 0.2%, respectively.5 Almost all subjects maintained normal values of alkaline phosphatase and total bilirubin with no case of jaundice and hepatocellular injury (“Hy’s law”) reported.'
https://www.ncbi.nlm...ubmed/18690992/
'However, post-marketing surveillance identified 406 cases with potential hepatotoxicity from duloxetine between 8/2004 and 8/2006.6 Of these, 58 cases were considered clinically significant. A careful review of these cases led to the following observations: (a) there was no dose-dependent increase in the incidence of hepatic injury, ( 
a large number of cases occurred between 2 and 8 weeks of therapy and 74% with onset within 16 weeks, © 31% had either pre-existing liver disease or clinical risk factors for liver disease, and (d) there were two fatal cases possibly related to duloxetine.'
https://www.ehealthm...balta/jaundice/
FDA statistics on side effects
"95,293 people reported to have side effects when taking Cymbalta.
Among them, 299 people (0.31%) have Jaundice"
Time on Cymbalta when people have Jaundice *:
⦁ < 1 month: 32.17 %
⦁ 1 - 6 months: 44.35 %
⦁ 6 - 12 months: 5.22 %
⦁ 1 - 2 years: 5.22 %
⦁ 2 - 5 years: 13.04 %
⦁ 5 - 10 years: 0.0 %
⦁ 10+ years: 0.0 %
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Cymbalta and the skin
https://dailymed.nlm...f2-c185fbad64ba
From the drug insert for Cymbalta...
(side effects) Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral (Soreness and sensativity in the mouth)
Severe Skin Reactions — Caution patients that CYMBALTA may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions (5.6)].
5.6 Severe Skin Reactions
Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.
CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.
http://www.mayoclini...es/dxc-20317107
Details on SJS can be found at the above site.
Stevens-Johnson syndrome
Stevens-Johnson syndrome signs and symptoms include:
⦁ Fever
⦁ Unexplained widespread skin pain
⦁ A red or purple skin rash that spreads
⦁ Blisters on your skin and the mucous membranes of your mouth, nose, eyes and genitals
⦁ Shedding of your skin within days after blisters form
If you have Stevens-Johnson syndrome, several days before the rash develops you may experience:
⦁ Fever
⦁ Sore mouth and throat
⦁ Fatigue
⦁ Cough
⦁ Burning eyes
When to see a doctor
Stevens-Johnson syndrome requires immediate medical attention. Seek emergency medical care if you experience signs and symptoms of this condition.
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Cymbalta and Seizures and Sodium
https://www.ncbi.nlm...les/PMC2963463/
We believe that this is the first reported case in which a person developed duloxetine withdrawal seizure secondary to deranged electrolytes after abruptly stopping duloxetine.
Her sodium was 134, potassium was 2.5, chloride 86, glucose 110, calcium 9, and magnesium 1.5.
https://www.ncbi.nlm...les/PMC3229538/
Although the risk of seizures with antidepressants is generally very low, the association with overdose is well established. However, the molecular mechanisms by which antidepressants cause seizures have not been clarified. GIRK2 knockout mice exhibit spontaneous seizures and are more susceptible to seizures induced by pentylenetetrazol than wild-type mice. The risk of seizures in overdoses with sertraline, duloxetine, mianserin, and venlafaxine significantly increases, and amoxapine overdose is more likely to cause seizures. Brain levels of the drugs in overdose cases may be considerably higher than levels during treatment at therapeutic doses, suggesting significant inhibition of neuronal GIRK channels by the drugs. Additionally, other types of K+ channels are inhibited by antidepressants at micromolar concentrations, that is, the two-pore-domain K+ channel, TREK-1 for sertraline and voltage-gated K+ channels for amoxapine and mianserin. Therefore, the inhibition of GIRK channels by the drugs after overdose together with the different types of K+ channels may contribute to increased seizure activity and the occurrence of other neurological side effects by increasing neuronal excitability.
Note - GIRK2 is a K+ ion regulatory mechinism.
https://www.ncbi.nlm...pubmed/16534127
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
Description of antidiuretic hormone
Kidney
Aantidiuretic hormone has three main effects:
Increasing the water permeability of initial and cortical collecting tubules and inner medullary collecting duct in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis.
Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct.
Acute increase of sodium absorption across the ascending loop of henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct.
Note - This could severely impact sodium and potassium levels in the blood stream.
From article - "We describe a woman who developed severe hyponatremia on exposure to duloxetine and recurrence on inadvertent rechallenge, suggesting the causative relationship of this drug to hyponatremia. "
Hyponatremia - is a low sodium level in the blood.
http://www.ncbi.nlm....pubmed/22306002
Generalized tonic-clonic seizure secondary to duloxetine poisoning: a short report with favorable out come.
Note - Tonic–clonic seizures (formerly known as grand mal seizures) are a type of generalized seizure that affects the entire brain. Tonic–clonic seizures are the seizure type most commonly associated with epilepsy and seizures in general, though it is a misconception that they are the only type.
https://www.ncbi.nlm...les/PMC2963463/
Duloxetine Withdrawal Seizure
She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep. She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.
https://www.accessda...s011s013lbl.pdfFDA
Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
Note this article links Cymbalta to Hyponatremia caused by inappropriate antidiuretic hormone secretion.
Medical research articles linking Cymbalta to Hyponatremia
http://www.ncbi.nlm....pubmed/23075738
https://www.ncbi.nlm...les/PMC3285747/
https://www.ehealthm.../hyponatraemia/
https://www.ncbi.nlm...pubmed/25538343
https://www.ncbi.nlm...pubmed/25911354
https://www.ncbi.nlm...pubmed/18562431
https://www.ncbi.nlm...pubmed/17224730
https://www.ncbi.nlm...pubmed/17502788
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Cymbalta and seizures
1) Comments by Members
Grand Mal Seizure And Mouth Spasms ?
Posted by justsayno on 02 April 2017 - 07:58 PM in How to Find Support
Was trying to work it out tonight. Looking for any patterns / similarities etc
Only obvious thing being that both seizures occurred after a dosage drop from 40 to 30 mg.
Grand Mal Seizure And Mouth Spasms ?
Posted by justsayno on 01 April 2017 - 02:26 PM in How to Find Support
Hi Gail
Far as I am aware No. In 28 years I've never had any seizures until I began taking Cymbalta.
Bead Counting Advice Doesn't Jive With My Capsule Contents
Posted by PtldFrank on 04 September 2016 - 04:44 PM in Weaning Off Cymbalta
Vinpin,
Regarding seizures, that's a subject I do have personal experience with. The good news is that I'm seizure free for more than 10 years. The bad news is that I had half a dozen gran mal seizures in the 12 years prior, starting with wellbutrin. I tend to believe the seizures all came from the various meds (15-20 combinations) I went through. The only thing that seems to have stopped the seizures is the anti seizure medicine Keppra.
Involuntary Cold Turkey From 120Mg
Posted by Cassandra on 13 February 2015 - 10:32 AM in What are you feeling?
Hello world, this is Cassandra. It's been a rough month since I quit cymbalta and I think it'd be best to start from the very beginning.
I have been experiencing major depression as long as I can remember, at least from the age of 9 which is where my earliest memories are. I was put on my first antidepressant--celexa--5 or six years ago. I had been depressed before but when I started medication it just got worse. Five/six months ago I was put on cymbalta, first 60 mg then 120, and it got worse. I became violently suicidal and after a course of 12 ect treatments I attempted suicide by taking 2 bottles of cymbalta at once (my insurance had just switched me to where I could only get my meds in a 90 day supply--bad, bad idea to give someone who's suicidal a giant bag of meds.)
I woke up having seizures that went on for hours, and then on and off for a few days. When I got to the hospital, I was hallucinating, and couldn't stand or eat for days. I learned how to walk again and a month later I can ride my bike again.
Listing The Positive Events Daily Through My Cymbalta Withdrawl
Posted by FiveNotions on 24 December 2014 - 09:42 AM in ARE YOU NEW HERE? Words from the wise about Cymbalta
I was just talking with a friend about where I was last year this time ... compared to this year ... and it seemed more than worthy of a post in our "Positives" thread ...
Last year this time I was about 19 days into hard, cold turkey withdrawal ... I was overwhelmed with vertigo and nausea, confined almost totally to bed, and crawling to the bathroom to puke ... at one point, I just took my blanket and pillow in there and slept/lay curled up on the floor (less far to travel) ... I was unable to eat any solid foods, not even crackers ... and was living on broth and herb tea and water (didn't make for much to puke up, but I still did) ...
I was having constant muscle spasms, and had a couple of seizures (at least I assume that's what they were, I just blacked out and woke up on the floor) ... I was having auditory and visual hallucinations, constant cold, dripping sweats, and horrid general body aches and pains .... couldn't sleep much at all, just an hour or so at a time ... I hadn't showered, washed my hair, changed clothes, or changed my sheets, once ... and I simply did not care ...
Article: Duloxetine Withdrawal Seizure [Cold Turkey Withdrawal]
Posted by FiveNotions on 03 January 2015 - 09:32 AM in Cymbalta in the News
I think I had at least 1, possibly 2, seizures during hard, cold turkey withdrawal ... but don't know for sure, was alone and woke up on the floor ... yet another reason not to quit this poison cold turkey!
Duloxetine Withdrawal Seizure [full text]
Psychiatry (Sept 2006)
http://www.ncbi.nlm....les/PMC2963463/
From the article:
Much has been written about the use and side effects profile of duloxetine (Cymbalta®). We report a case of a patient who had generalized tonic clonic seizures after abruptly stopping duloxetine.
Case report. Ms. X was a 59-year-old Caucasian woman with a diagnosis of major depressive disorder recurrent severe without psychotic feature. She was stabilized on duloxetine 90mg p.o. daily.
She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep.
She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.
Urine drug screen was negative. Urinalysis was negative. Complete blood count (CBC) was normal. Her sodium was 134, potassium was 2.5, chloride 86, glucose 110, calcium 9, and magnesium 1.5. Her blood urea nitrogen (BUN) and creatinine were normal. Her liver function tests were normal except mildly elevated alkaline phosphatase of 126. Computed tomography (CT) scan of her head was negative. There was no sign of infection at the point of admission. She was stabilized and was then started on a different antidepressant due to her history of nonadherence. She had no further seizures during her hospital stay.
Seizure?
Posted by sarahb on 04 April 2014 - 10:59 AM in What are you feeling?
My mother has been on Cymbalta I think 90mg and she recently started having seizures. I wonder if there could be any correlation. I'm the one who was on it 5 days and found your group and has decided to get off. Now my thoughts are with my mom. I know different things about her health are shorting her health but I hate to think what this drug is doing to her and God forbid she needs to get off.
And Here I Am- Am I Screwed Forever?
Posted by jenniesue on 09 December 2013 - 12:49 PM in ARE YOU NEW HERE? Words from the wise about Cymbalta
The DVT/Blood Clots were after I lost a pregnancy. Yes I was placed on Cymbalta for pain. The seizures I had started within 2 weeks of taking Cymbalta. Yes I have discussed all issues with my Dr. and they give me a diagnosis of something else, and have told me just keep taking the Cymbalta. Where do I start to get off of this evil med? I go to see my Dr. Monday Dec 15.
Seen The New Commercials?
Posted by Pixi on 10 June 2012 - 02:32 AM in Cymbalta in the News
I'd thought I was unsubscribed...but this thing emailed me for a reply so here goes. I can't believe it's almost a year to the day since I made the post on here. That means I've been totally Cymbalta free for 6 months! I took my healthcare into my own hands & I'm glad I had the fortitude to go through this & come out as well as I have.
I'm taking nothing for depression/neuropathy and still having the odd brain zap & dizziness - my "Cymbalta moments" as I call it. . Still having seizures at night, bouts of horrible dementia and just wish I'd never listened to the Doctors & allowed myself to be their labrat for this evil drug. Depression is still much better off it and bladder control is almost back to normal. The ONLY way to go is wean slowly, count the grains even tho it's tedious - over months, even if you're only just on it a few weeks, start to cut it down really slowly - your brain is way more delicate than you know. This shit does pretty weird things to you - that's how it's supposed to work - alter your neurology. Don't let them mess with you. It caused me DID/MPD, made my diabetic neuropathy 100 times worse & a host of other shit I've probably posted about elsewhere on this forum.
Seizures From Cymbalta
Posted by Namaste on 02 May 2012 - 02:04 AM in Weaning Off Cymbalta
Doctor changed celexa to cymbalta And was ok with it for a month and
I started Having hives, itching and bruises. My doctor stopped cymbalta and gave me prednisone. Then i started having seizures where i was fully aware of what was happening so I'm now on lamictal for seizures. Anyone of you having the same experience?
My Chapter Of Hell
Posted by distill on 06 December 2011 - 02:55 AM in ARE YOU NEW HERE? Words from the wise about Cymbalta
I have already wrote this once, but if I can help out another person then I've done what I set out to do.
I know some people have done great while taking it but the withdrawal is what gets them. I was not depressed, I was injured on the job crush three disc in my lower back. I was put on it for sciatic help.
I had a house, cars, and my best friend for a fiance. Within two weeks of taking it I lost my mind. Manic aggression, seizures, nightmares, etc. I did things I never wouldve done before this. Its like i either knew what i was doing and didnt care or i flat out dont remember. We were losing the house and my demeanor drove her away. Workers comp denied paying for all psychological meds and I flat out couldn't afford $400 for 90days. That was in January of this year.
Neuropathy As A Side Effect?
Posted by cookie on 28 November 2011 - 11:57 AM in Weaning Off Cymbalta
Dear Pixi
I took cymbalta for depression, other than than I was a pretty healthy person. After 6 years of taking it, I have sugar problems and now I am experiencing prickling sensations and pin & needles. I also have problems remembering names. I also experienced seizures and problems with my joints which I never had prior to the medication
Check In On Your Progress Here!
Posted by CindiEponabri on 16 October 2011 - 01:31 AM in Weaning Off Cymbalta
1) Method you're using
Counting bead method, kinda... I take out about 1/4 of the beads out of one of the two capsules for each day's dosage, for a week. The following week it will be 1/2 of the beads of one capsule.
2) Starting dose
120mg
3) Current dose
105mg (roughly)
4) Withdrawal symptoms you're having
more pain, anxiety, dizziness, tired, nausea, cold/flu symptoms, nightmares, itching,
5) Things that have improved.
Seizures.. we had thought they were being caused from the Oxycotin, but now I see it was from the Cymbalta, because for the most part they are now gone. I have a little one every now and then.
My Story
Posted by cookie on 26 July 2011 - 02:25 PM in Weaning Off Cymbalta
Dear Imdone:
.....However I learned to differentiate the initiall symptoms from withdrawals. I took the medication for severe depression. When I reduced dose I started experiencing asthma, itching, joint pain, problems finding words to talk and comprehending language, dizziness, vomiting, seizures, facial tics, sensitivity to noises and light, tremors, allergies, sore throat, etc which I definitely didn´t have when my depression appeared 6 years ago.
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2) Drug insert from Eli Lilley for Cymbalta
https://dailymed.nlm...f2-c185fbad64ba
5.7 Discontinuation of Treatment with CYMBALTA
Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.7)].
6.12 Postmarketing Spontaneous Reports
The following adverse reactions have been identified during post approval use of CYMBALTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions reported since market introduction ....., seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
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3) Medical Research on Seizures and Cymbalta.
Other info on seizures,
https://www.ncbi.nlm...les/PMC3229538/
"Although the risk of seizures with antidepressants is generally very low, the association with overdose is well established [80]. However, the molecular mechanisms by which antidepressants cause seizures have not been clarified. GIRK2 knockout mice exhibit spontaneous seizures and are more susceptible to seizures induced by pentylenetetrazol than wild-type mice [37]. The risk of seizures in overdoses with sertraline, duloxetine, mianserin, and venlafaxine significantly increases [80]–[82], and amoxapine overdose is more likely to cause seizures [83]. "
80. Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract. 2005;59:1435–1440. [PubMed]
81. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Q J Med. 2003;96:369–374. [PubMed]
82. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277–285. [PubMed]
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https://www.ncbi.nlm...les/PMC4683813/
"Epilepsy is a serious condition which can profoundly affect an individual’s life. While there is some evidence to suggest an association between antidepressant use and epilepsy and seizures it is conflicting and not conclusive. "
"Conclusions
Risk of epilepsy/seizures is significantly increased for all classes of antidepressant. There is a need for individual risk-benefit assessments in patients being considered for antidepressant treatment, especially those with ongoing mild depression or with additional risk factors. Residual confounding and indication bias may influence our results, so confirmation may be required from additional studies."
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https://www.ncbi.nlm...pubmed/16534127
Neurology. 2006 Mar 14;66(5):773-4.
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
Maramattom BV1.
"The syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia is a well known side effect of older selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline, fluoxetine, citalopram, escitalopram, and fluvoxamine.1,2 The frequency of hyponatremia is around 8 per 1,000 among elderly women receiving fluoxetine.2 Although the second-generation dual blockers, selective serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine, are touted to have a wider therapeutic index, hyponatremia is encountered even with venlafaxine. To date, Medline searches do not reveal any reports of hyponatremia associated with duloxetine. We describe a woman who developed severe hyponatremia on exposure to duloxetine and recurrence on inadvertent rechallenge, suggesting the causative relationship of this drug to hyponatremia. "
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http://www.psychforu...topic69139.html
This is a thread about seizures and Cymbalta you might want to check out.
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http://www.ehealthme...mbalta/seizure/
95,293 people reported to have side effects when taking Cymbalta.
Among them, 1,077 people (1.13%) have Seizures
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https://www.ncbi.nlm...pubmed/16534127
Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures.
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http://www.ncbi.nlm....pubmed/22306002
Generalized tonic-clonic seizure secondary to duloxetine poisoning: a short report with favorable out come.
Abstract
Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake (SNRI) with a weak activity over dopamine reuptake used in the treatment of major depressive disorder. Daily doses of 60 mg are effective in treatment of major depression. There are few cases of isolated duloxetine overdose in humans. We think this is the first report of a generalized tonic-clonic seizure following isolated duloxetine poisoning with a very high dosage.
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https://www.ncbi.nlm...les/PMC2963463/
Duloxetine Withdrawal Seizure
She came to the emergency room with complaints of nausea, clear liquid vomitus, anxiety, “electical sensation” inside the body, restlessness, decreased liquid intake, abdominal pain, and decreased sleep. She stopped taking her duloxetine two days previoiusly. She had two generalized tonic clonic seizures 20 minutes apart in the hospital.
=============================================================
4) Misc.
Benzos can trigger seizures.
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Hyponatremia
Note - Hyponatremia is a know cause of grand mal seizures, but low potassium is not. Cymbalta can cause Hyponatremia (low serum sodium levels). See below
https://www.accessda...s011s013lbl.pdfFDA
Hyponatremia — Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.
http://www.ncbi.nlm....pubmed/23075738
A case of severe hyponatremia induced by duloxetine and ziprasidone.
https://www.ncbi.nlm...les/PMC3285747/
Rapid-Onset Hyponatremia Induced by Duloxetine in a Middle-Aged Male with Depression and Somatic Symptoms
https://www.ehealthm.../hyponatraemia/
95,293 people reported to have side effects when taking Cymbalta.
Among them, 649 people (0.68%) have Hyponatraemia
https://www.ncbi.nlm...pubmed/25538343
Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics.
https://www.ncbi.nlm...pubmed/25911354
Syndrome of inappropriate antidiuretic hormone secretion: a story of duloxetine-induced hyponatraemia.
https://www.ncbi.nlm...pubmed/18562431
Severe and symptomatic hyponatremia following duloxetine treatment.
https://www.ncbi.nlm...pubmed/17224730
Duloxetine and hyponatremia: a report of 5 cases.
https://www.ncbi.nlm...pubmed/17502788
Recurrent hyponatremia after substitution of citalopram with duloxetine.
And more....
https://www.mayoclin...ms/con-20031445
Mayo Clinic
Hyponatremia signs and symptoms may include:
⦁ Nausea and vomiting
⦁ Headache
⦁ Confusion
⦁ Loss of energy and fatigue
⦁ Restlessness and irritability
⦁ Muscle weakness, spasms or cramps
⦁ Seizures
⦁ Coma
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Drugs.com
Applies to: Wellbutrin (bupropion), Cymbalta (duloxetine)
Talk to your doctor before using buPROPion together with DULoxetine. Combining these medications may increase the risk of seizures, which may occur rarely with either medication. In addition, buPROPion can increase the blood levels of DULoxetine, which may increase other side effects. You may be more likely to experience seizures with these medications if you are elderly, undergoing alcohol or drug withdrawal, have a history of seizures, or have a condition affecting the central nervous system such as a brain tumor or head trauma.
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Cymbalta's effect on neurotranmitters in the brain.
http://www.ncbi.nlm....les/PMC2626928/
http://www.ncbi.nlm....pubmed/18751896
http://www.ncbi.nlm....pubmed/15991911
http://www.ncbi.nlm..../pubmed/8592129
http://www.ncbi.nlm..../pubmed/7576005
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Cymbalta Fat soluble & tissue absorbtion.
From:
http://www.drugs.com/pro/cymbalta.html
"Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water."
Note - From the structure we can see that the compound is primarily non-polar and therefore should be fat soluble.
From:
http://www.drugbank.ca/drugs/DB00476
Water Solubility = 0.00296 mg/mL (Vertually insoluble) ALOGPS
Note - If it is not water suluble (polar (has a negative or positive charge)) then it is non-polar (not charged) and would be lipid soluble.
From:
http://www.selleckch...l-cymbalta.html
Chemical Information
Solubility (25°C) * In vitro DMSO 67 mg/mL (200.67 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
Note - Dissolves well in DMSO a relatively nonpolar solvent.
From:
http://toxwiki.wikis....com/Duloxetine
Soluble in dimethylformamide (nonpolar) and water.
From:
https://www.ncbi.nlm...les/PMC3299448/
Table I
Amount of Solid Lipid (fat) Required to Solubilize 20 mg of DLX and Percent Partitioning of DLX in Lipid vs Water
Solid lipid Amount (mg) % Partitioning
Glyceryl monostearates 400 92
Glyceryl behenate 700 33
Glyceryl palmitostearate 650 60
Geleol 450 60
Gelucire 44/14 800 –
From 33% to 92% lipid (fat) soluble.
Ta
https://oup.silverch...BIA4LVPAVW3QbleII.
http://www.ema.europ...776.pdfstmortemTissue
Duloxetine was highly bound to proteins in plasma, the mean percent bound to human plasma proteins at a duloxetine concentration of 150.2 ng/mL being 95.9%
Duloxetine was present in high concentrations in the stomach and intestinal contents at 3 to 12 hours
postdose. Kidney, liver, and lung contained the highest tissue concentrations.Overall, the liver was determined to be the primary organ responsible for the metabolism of duloxetine. Distribution of Duloxetine
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PSSD
J Clin Psychopharmacol. 2015 Jun;35(3):273-8. doi: 10.1097/JCP.0000000000000300.
Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship.
· Abstract
Emerging evidence suggests that sexual dysfunction emerging during treatment with selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some patients beyond drug discontinuation (post-SSRI sexual dysfunction [PSSD]). We sought to identify and characterize a series of such cases and explore possible explanatory factors and exposure-response relationship. Subjects who responded to an invitation in a forum dedicated to PSSD filled out a survey via online software. Case probability was defined according to the following 3 categories of increasing presumed likelihood of PSSD. Noncases did not meet the criteria for possible cases. Possible cases were subjects with normal pretreatment sexual function who first experienced sexual disturbances while using a single SSRI/SNRI, which did not resolve upon drug discontinuation for 1 month or longer as indicated by Arizona Sexual Experience Scale scores. High-probability cases were also younger than 50-year-olds; did not have confounding medical conditions, medications, or drug use; and had normal scores on the Hospital Anxiety and Depression Scale. Five hundred thirty-two (532) subjects completed the survey, among which 183 possible cases were identified, including 23 high-probability cases. Female sex, genital anesthesia, and depression predicted current sexual dysfunction severity, but dose/defined daily dose ratio and anxiety did not. Genital anesthesia did not correlate with depression or anxiety, but pleasureless orgasm was an independent predictor of both depression and case probability. Limitations of the study include retrospective design and selection and report biases that do not allow generalization or estimation of incidence. However, our findings add to previous reports and support the existence of PSSD, which may not be fully explained by alternative nonpharmacological factors related to sexual dysfunction, including depression and anxiety.
Eur J Pharmacol. 2015 Apr 15;753:263-8. doi: 10.1016/j.ejphar.2014.11.031. Epub 2014 Dec 4.
Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels.
· Abstract
· Treatment of paroxetine-induced penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) by Low-power Laser Irradiation (LPLI) is unknown in medical literature. The aim of the current article is to report partial efficacy of LPLI for paroxetine-induced persistent penile anesthesia. We report on a male patient who presented with a history of reversible loss of smell, taste and skin sensitivity occurring within a week after start of 20mg/day paroxetine-hemihydrate for a depressive period. Concurrently, patient suffered from penile anesthesia, scrotum hypesthesia, anejaculation and erectile difficulties with normal sexual desire. During 2.5 years of paroxetine treatment and throughout 2 years after paroxetine discontinuation, genital and sexual complaints persisted. Penile anesthesia was treated by LPLI with single and multi diode pulsed laser probes. After 20 LPLI-treatment sessions of 15min each, patient reported partial return of penile touch and temperature sensation. Clinical improvement of glans penis sensitivity was reported to 20% and 40%, compared to pre-paroxetine treatment penile sensitivity during erect and flaccid states, respectively. However, anejaculation and erectile difficulties remained unchanged. Briefly, in the current patient with early onset of PSSD, LPLI treatment reduced paroxetine-induced penile anesthesia. It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.
The Open Women' Health Journal, 2007, 1, 1-3
Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone
Robert P. Kauffman* and Amanda Murdock Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, School of Medicine, 1400 Coulter Drive, Amarillo, Texas 79106 USA
The Open Psychology Journal, 2008, 1, 42-50
1874-3501/08 2008 Bentham Open
Open Access
Persistence of Sexual Dysfunction Side Effects after Discontinuation of
Antidepressant Medications: Emerging Evidence
Audrey S. Bahrick*
http://pssd.nl/Persi... medication.pdf
Persistent Sexual Dysfunction after Discontinuation of Selective
Serotonin Reuptake Inhibitors
Antonei Csoka, PhD,* Audrey Bahrick, PhD,† and Olli-Pekka Mehtonen, MD‡
*University of Pittsburgh––Medicine, Pittsburgh, PA, USA; †University of Iowa—University Counseling Service, Iowa City,
IA, USA; ‡Kaivanto Psychiatric Hospital—Psychiatry, Helsinki, Finland
DOI: 10.1111/j.1743-6109.2007.00630.x
A B S T R A C T
Introduction. Sexual dysfunctions such as low libido, anorgasmia, genital anesthesia, and erectile dysfunction are
very common in patients taking selective serotonin reuptake inhibitors (SSRIs). It has been assumed that these side
effects always resolve after discontinuing treatment, but recently, four cases were presented in which sexual function
did not return to baseline. Here, we describe three more cases.
Case #1: A 29-year-old with apparently permanent erectile dysfunction after taking fluoxetine 20 mg once daily for
a 4-month period in 1996.
Case #2: A 44-year-old male with persistent loss of libido, genital anesthesia, ejaculatory anhedonia, and erectile
dysfunction after taking 20-mg once daily citalopram for 18 months.
Case #3: A 28-year-old male with persistent loss of libido, genital anesthesia, and ejaculatory anhedonia since
taking several different SSRIs over a 2-year period from 2003–2005.
Results. No psychological issues related to sexuality were found in any of the three cases, and all common causes of
sexual dysfunction such as decreased testosterone, increased prolactin or diabetes were ruled out. Erectile capacity
is temporarily restored for Case #1 with injectable alprostadil, and for Case #2 with oral sildenafil, but their other
symptoms remain. Case #3 has had some reversal of symptoms with extended-release methylphenidate, although it
is not yet known if these prosexual effects will persist when the drug is discontinued.
Conclusion. SSRIs can cause long-term effects on all aspects of the sexual response cycle that may persist after they
are discontinued. Mechanistic hypotheses including persistent endocrine and epigenetic gene expression alterations
were briefly discussed. Csoka A, Bahrick A, and Mehtonen O-P. Persistent sexual dysfunction after discontinuation
of selective serotonin reuptake inhibitors. J Sex Med 2008;5:227–233.
http://psychrights.o...aetal(2007).pdf
OR
http://onlinelibrary...07.00630.x/full
One hundred and twenty cases of enduring
sexual dysfunction following treatment
Carys Hogana, Joanna Le Nourya, David Healya,∗ and Derelie Manginb
aNorth Wales Department of Psychological Medicine, Bangor, Wales, UK
bDavid Braley & Nancy Gordon Chair of Family Medicine, Department of Family Medicine,
McMaster University, ON, Canada
Received 17 February 2014
Accepted 21 April 2014
Abstract.
BACKGROUND: There have been reports for over a decade linking serotonin reuptake inhibitors, finasteride and isotretinoin
with enduring sexual dysfunction after treatment stops.
OBJECTIVE: To explore the clinical pictures linked to all 3 drugs.
METHODS: We have selected 120 reports to RxISK.org reporting the problem and mined these for data on age, gender, drug
of use, and impact of the problem.
RESULTS: The data make it clear that the three drugs show extensive overlap in symptom profile, regardless of sex or country
of origin.
CONCLUSIONS: The availability of 120 reports from over 20 countries add to the case for the validity of the syndrome. This is
severe and enduring condition can result in death. An understanding of its physiology and an approach to treatment are needed.
http://wp.rxisk.org/...Is-and-PSSD.pdf
The prescriber information for Prozac from Eli Lilly's website. Halfway through the 15th page is a clause which reads, “Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.
Journal of Contemporary Psychotherapy June 2009, Volume 39, Issue 2, pp 135-143
Sexual Side Effects of Antidepressant Medications: An Informed Consent Accountability Gap
Abstract
Sexual side effects of antidepressant medications are far more common than initially reported, and their scope, quality, and duration remain poorly captured in the literature. Antidepressant treatment emergent sexual dysfunctions may decrease clients’ quality of life, complicate psychotherapy, and damage the treatment alliance. Potential damage to the treatment alliance is greatest when clients have not been adequately informed of risks related to sexual side effects. It had previously been assumed that sexual side effects always resolve shortly after medications are discontinued. Emerging evidence, however, suggests that in some individuals, sexual dysfunction side effects may persist indefinitely. The authors argue that all psychologists should be well-informed about sexual side effects risks of antidepressant medications, should routinely conduct a pre-medication baseline assessment of sexual functioning, and take an active role in the informed consent process.
Wikipedia article
http://www.thefullwi...ual_dysfunction
https://www.ncbi.nlm...pubmed/25483212
Eur J Pharmacol. 2015 Apr 15;753:263-8. doi: 10.1016/j.ejphar.2014.11.031. Epub 2014 Dec 4.
Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels.
· Abstract
· Treatment of paroxetine-induced penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) by Low-power Laser Irradiation (LPLI) is unknown in medical literature. The aim of the current article is to report partial efficacy of LPLI for paroxetine-induced persistent penile anesthesia. We report on a male patient who presented with a history of reversible loss of smell, taste and skin sensitivity occurring within a week after start of 20mg/day paroxetine-hemihydrate for a depressive period. Concurrently, patient suffered from penile anesthesia, scrotum hypesthesia, anejaculation and erectile difficulties with normal sexual desire. During 2.5 years of paroxetine treatment and throughout 2 years after paroxetine discontinuation, genital and sexual complaints persisted. Penile anesthesia was treated by LPLI with single and multi diode pulsed laser probes. After 20 LPLI-treatment sessions of 15min each, patient reported partial return of penile touch and temperature sensation. Clinical improvement of glans penis sensitivity was reported to 20% and 40%, compared to pre-paroxetine treatment penile sensitivity during erect and flaccid states, respectively. However, anejaculation and erectile difficulties remained unchanged. Briefly, in the current patient with early onset of PSSD, LPLI treatment reduced paroxetine-induced penile anesthesia. It is hypothesized that SSRI treatment induces disturbances of transient receptor potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. It is further hypothesized that there are two types of PSSD, one of which occurs soon after the start of SSRI treatment.
https://www.ncbi.nlm...pubmed/25815755
Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship.
Emerging evidence suggests that sexual dysfunction emerging during treatment with selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some patients beyond drug discontinuation (post-SSRI sexual dysfunction [PSSD]). We sought to identify and characterize a series of such cases and explore possible explanatory factors and exposure-response relationship. Subjects who responded to an invitation in a forum dedicated to PSSD filled out a survey via online software. Case probability was defined according to the following 3 categories of increasing presumed likelihood of PSSD. Noncases did not meet the criteria for possible cases. Possible cases were subjects with normal pretreatment sexual function who first experienced sexual disturbances while using a single SSRI/SNRI, which did not resolve upon drug discontinuation for 1 month or longer as indicated by Arizona Sexual Experience Scale scores. High-probability cases were also younger than 50-year-olds; did not have confounding medical conditions, medications, or drug use; and had normal scores on the Hospital Anxiety and Depression Scale. Five hundred thirty-two (532) subjects completed the survey, among which 183 possible cases were identified, including 23 high-probability cases. Female sex, genital anesthesia, and depression predicted current sexual dysfunction severity, but dose/defined daily dose ratio and anxiety did not. Genital anesthesia did not correlate with depression or anxiety, but pleasureless orgasm was an independent predictor of both depression and case probability. Limitations of the study include retrospective design and selection and report biases that do not allow generalization or estimation of incidence. However, our findings add to previous reports and support the existence of PSSD, which may not be fully explained by alternative nonpharmacological factors related to sexual dysfunction, including depression and anxiety.
https://www.ncbi.nlm...pubmed/28778697
Post-SSRI Sexual Dysfunction: A Literature Review.
https://www.ncbi.nlm...pubmed/28642048
Sex Med Rev. 2017 Oct;5(4):429-433. doi: 10.1016/j.sxmr.2017.05.002. Epub 2017 Jun 20.
Sexual Consequences of Post-SSRI Syndrome.
Abstract
INTRODUCTION:
Sexual dysfunctions are well-known side effects of selective serotonin reuptake inhibitor (SSRI) use. Altered libido, erectile dysfunction, vaginal dryness, ejaculatory disorders, and orgasmic problems are frequently reported by patients treated with SSRIs. Moreover, these antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely. These complaints are termed post-SSRI sexual dysfunctions (PSSD).
AIM:
To examine the existence of this clinical entity, possible theoretical mechanisms, possible risk factors, and possible treatment modalities.
METHODS:
Through literature research and clinical experience, the available information about PSSD is reviewed.
MAIN OUTCOME MEASURES:
Summary of the current literature with insights into possible causes and management options.
RESULTS:
There are some indications that antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely in some individuals. Although some or all sexual side effects that start with the use of SSRIs might continue after stopping the medication, other sexual complaints can develop. Decreased capacity to experience sexual pleasure is the most frequent characteristic of this syndrome.
CONCLUSION:
The research and understanding of PSSD remain limited and not well understood; however, the data support the existence of PSSD, which can have a substantial effect on the quality of life of these patients. More research is warranted to show the cause and possible mechanisms of PSSD that could lead to the correct diagnosis and treatment. Reisman Y. Sexual Consequences of Post-SSRI Syndrome. Sex Med Rev 2017;5:429-433.
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