A most interesting read. Especially this section. It is interesting to note that the author fails to refer to the contribution of sugar, salt, and other dietary items that can worsen anxiety.
Contributing factors to true treatment resistance
Once it has been established that an effective treatment has been adequately delivered and adhered to, there will remain a proportion of patients who have not remitted and a smaller proportion that remain quite symptomatic. Because there has been no equivalent of the STAR-D study for anxiety disorders, we do not have good data on the proportions of anxious patients who fail to remit or respond after adhering to adequately delivered treatment. However, the rates are likely to be similar to those seen in this landmark study of depression, ie, only 30% remit with initial treatment, and even after multiple treatments the remission rate is at best 60%. The clinician at this point needs to consider whether there are exogenous factors that are aggravating and/or maintaining anxiety, whether there may be a medical condition that is playing an important role, and last but not least, whether the diagnosis may be either wrong or incomplete, ie, whether there is another comorbidity present that is accounting for the poor response.
There are a number of anxiogenic factors that can contribute to anxiety. While many of these are quite obvious and may be routinely assessed by the clinician, patients may not always acknowledge them, or may minimize their severity and import. In the course of a complex intake done with limited available time, these factors are often glossed over quickly in order to cover more important diagnostic, course of illness and treatment response areas, and may come to the fore much later in the course of treatment.
Excess caffeine intake is rarely a “cause” of anxiety but is a frequent aggravator/amplifier.36 Patients will often have accompanying fatigue (perhaps as part of a comorbid depression), which is a driver of caffeine use, and if they do not experience symptom aggravation coincident with the timing of intake, they will minimize this. It is important to note that dependence on caffeine not only produces anxiety as a caffeine effect, but may produce this as a withdrawal effect, greatly confusing the picture.37
Moreover, patients often are not aware of the caffeine content of some beverages, eg, the patient who was drinking several cans of Mello Yello daily, believing it was a relaxant and was unaware of the amount of caffeine he was ingesting.
Over-the-counter cold preparations contain phenylpropylamine and pseudoephedrine, obvious stimulants. Yet patients with unexplained dyspnea may believe they have allergies and take these medications frequently in order to treat their anxiety symptom, further exacerbating their dyspnea and anxiety symptoms. The use of energy drinks with combinations of both caffeine and stimulants is another important example.
One night's total sleep deprivation has been shown to exacerbate panic,38 and relative sleep deprivation almost certainly plays an important role in aggravating anxiety. Relative deprivation of sleep likely plays an important role in the onset of first panic attack in college students, who may be stressed by exams, perhaps taking caffeine to stay up and study, and then losing substantial amounts of sleep.
While it is trite and tired to cite the importance of environmental stressors, it is less well appreciated that multiple studies examining anxiety outcomes have shown that life events, poor social support (Figure 3), and financial adversity are associated with inadequate or incomplete treatment response.39-41 I often will keep several figures showing these relationships on my desk and then show them to patients who are asking for an exclusively pharmacologic approach, to push for some way of either solving the specific life issues (using problem-solving therapy) or improving coping targeted toward these stressors.
Disturbed spouse and family relationships predict lack of remission in generalized anxiety disorder.40
“Social” drinking (we will discuss alcohol abuse later) is known to aggravate panic and likely other anxiety syndromes, as the short-acting effects of alcohol wear off rapidly and there is a rapid rebound to a state of hyperexcitability that may be more problematic for anxious patients. Because this can happen to some patients after only one or two drinks, they often do not even consider that it can be an important factor. Explanation of the simple physiology of this (rebound excitation after profound neuronal inhibition) will often convince them that alcohol may be sensitizing the neural circuits subserving their anxiety and that a trial period of abstinence is indicated.
With the progressive availability of m******** by both medicalization and now legalization in several states, clinicians need to be aware that this substance is also known to be associated with anxiety in some patients, though the exact causal relationship is unclear,42 and the extant research in this area is still quite limited because of previous restrictions. At the same time, m******** is often utilized as an anxiety “treatment” by some people, with preclinical studies of the anxiolytic effects of cannabadiol components providing a theoretical justification for this. Nonetheless, it should be fairly obvious that someone showing up in a clinician's office with bothersome anxiety who is using m******** frequently might want to consider reducing or eliminating this use to see if it is contributing to their anxiety.
While many returning veterans may be using m******** to “treat” PTSD and have been empowered by research showing reduced cannabinoid receptors on PET scan in patients with PTSD, it is also likely that agonist treatment will further reduce this receptor number, perhaps creating a vicious neurobiologic cycle.43
Unrecognized medical illness
It is much more frequent for anxiety disorders to be mistaken for medical illness than the converse. Thus, many anxious patients first have costly medical workups and procedures, usually focusing on cardiopulmonary, gastrointestinal, and otoneurologic systems as the explanation for these specific physical symptoms. It is rare in clinical practice that a medical condition will account for anxiety, but the probability goes up slightly if the anxiety has been refractory to treatment. A number of illnesses need to be considered.
Complex partial seizure disorder presenting with symptoms of depersonalization, paroxysmal anxiety, and rarely gastrointestinal symptoms should be considered, and a careful history looking for head trauma, including a history of playing contact sports and having concussions, is important. In a young woman with sudden paroxysmal anxiety, pulmonary embolus is often overlooked, even in emergency settings. Hyperthyroidism is commonly listed in most “medical causes of anxiety” lists, and is easy enough to screen for, but is not a common cause. The same can be said for pheochromocytoma, whose distinguishing characteristic is often referred to as “cold fear,” ie, prominent autonomic symptoms without strong subjective fear or anxiety.
In this author's experience evaluating refractory anxiety in over 1 000 patients, only one time was a definitive medical cause suspected and found: someone with odd symptoms of paroxysmal anxiety and depersonalization who was found to have a temporal lobe tumor. An additional question is whether the presence of comorbid medical illness might make treatment less effective. Our recent study of this issue showed that treatment effects are comparable in anxious patients with and without comorbid medical illness. However, anxious patients with comorbid medical illness have greater severity of anxiety than those without medical illness, and comparable change still leaves fewer of these patients meeting remission criteria.44
Wrong diagnosis, bipolar illness, and other mimics of anxiety
There are a number of other conditions that may present with prominent anxiety symptoms. The most common, of course, now re-emphasized in the DSM-5, is MDD. Some patients may actually deny depressed mood and only endorse anxious mood, yet may have multiple symptoms of MDD that they attribute to “anxiety,” ie, “of course I cannot sleep or eat, am exhausted, have no interest or enjoyment, and cannot concentrate.... you would too if you had to deal with this constant unremitting anxiety.” More importantly, recent analyses have suggested that comorbid anxiety as a symptom has more prognostic value than the presence of a comorbid anxiety disorder,45 and that “spectrum” anxiety symptoms that include separation anxiety have similar import.46 While we have made major progress in differentiating anxiety into different syndromes and disorders with successive versions of the DSM, we may have to go “back to the future” as DSM-5 did in highlighting the prognostic importance of anxiety as a more undifferentiated symptom. This particular cause of refractory anxiety is uncommonly encountered because first-line antidepressant treatment will be effective for both mood and anxiety disorders. But it can be seen in patients treated with benzodiazepines alone, or in anxious depressions refractory to first-line antidepressant treatment. Interestingly, in contrast to most of the literature showing that anxiety predicts poorer outcome in depressive illness, the acute beneficial effects of intravenous ketamine are greater with the anxious depression subtype.47 The distinction between depression and anxiety in these comorbid cases becomes more important in educating patients about refractory anxiety, because recommending a depression-specific treatment (eg, in severe cases, ECT) often causes patients to argue that “you keep talking about depression, but my problem is anxiety.”
However, perhaps the most important diagnostic mimic seen routinely in practice, which tends to collect patients with refractory anxiety, is undiagnosed bipolar illness, most often bipolar 2 or “bipolar spectrum” illness. Such patients may not endorse or report typical hypomania and may have mood states that alternate between periodic retarded depressions and anxious dysphoric mixed states. The DSM-5 has made this differential diagnosis even harder, because, while it allows an anxious distress modifier for bipolar patients, it has removed as a core feature from mixed mania, what some experts see as the most important symptom,48 that of severe internal agitation and restlessness (which in turn contributes to dysphoric mood, erratic concentration, irritability, insomnia, and anorexia).
What is the supporting evidence for this concept? In addition to the high prevalence of anxiety disorders in bipolar illness (50% to 75% lifetime),49 studies have documented that in those with comorbid anxiety and bipolar disorders, the anxiety disorder occurs an average of 3 years earlier,49 and that the presence of an anxiety disorder predicts the transition from a diagnosis of major depression to bipolar illness in adults.50,51 Additionally, mania or mixed states, especially when occurring in the course of a rapid-cycling bipolar 2 disorder, may be misdiagnosed as anxiety states.52 Interestingly, children of bipolar parents treated for anxiety with antidepressants have a high rate of adverse responses including increased agitation and irritability.53 This may indicate what is often called a “treatment emergent affective switch.”54 Refractory patients in this category may also report rapid improvement on antidepressants that is not sustained beyond a few weeks or months at the most, and a stair-step pattern of responding, and then losing response, to multiple changes in antidepressants. Only recently are experts considering the possibility that antidepressants are overused and may be harmful to some bipolar patients.55 Some of these patients may report inability to tolerate antidepressants and need for benzodiazepines which can prompt clinician concern about abuse and or psychological dependence, when it only means these agents are far more tolerable for someone in the midst of a mixed state. The study of mixed states has been difficult, and the state of the art in a recent review leaves much that is wanting.56
Unfortunately, this differential diagnosis can be vexing for the clinician wedded to a strict interpretation of the diagnostic criteria for bipolar illness, due to the absence of clearly defined mania or hypomania. But attention to other features thought to indicate a soft bipolar condition will greatly improve the probability of diagnosis. These include the following: a history of post-partum depression, a family history of bipolar illness, agitation with antidepressants, rapid (within days) response to antidepressants, frequent loss of antidepressant effects, brief psychotic/paranoid episodes, and early-onset depression.57 Treatment with mood stabilizers and atypical antipsychotics often has major benefit in these patients. Recent cases have included a patient with early-onset panic attacks and subsequent development of agoraphobia, an intensive course of CBT, anxiety remission but then unexplained bouts of panic despite “working” a CBT program. Further inquiry revealed an accompanying loss of anti-panic effect to an SSRI requiring a second antidepressant, and then when this was lost, a switch to an SNRI that caused rapid improvement in days, but a loss of effect in several months. The panic breakthrough occurred briefly during these apparent remissions. Following this, there were more depressive episodes. Treatment with the anticonvulsant oxcarbazepine resulted in sustained remission.
Substance use disorder is an important comorbidity in patients with primary anxiety disorders and often makes it difficult to distinguish between naturallyoccurring alterations in anxiety and those induced by substance use or withdrawal. Anxiety can occur as part of withdrawal from multiple substances, especially alcohol, m******** and opiates, and as a symptom of intoxication with m********, psychedelics, cocaine, and other stimulants. Substance use is often unrecognized in ambulatory settings, where clinicians assume that most patients with this problem are already being treated in specialty or inpatient settings. Ambulatory clinicians rarely obtain a urine drug screen as part of a routine intake evaluation, much less order some of the newer tests capable of assessing recent alcohol use. Screening measures like the AUDIT-C are often useful to assess problem alcohol use or abuse because it contains only three questions on use frequency and quantity, has standardized cutoffs, and is not viewed with suspicion bymost heavy alcohol users who think their use amount may be “normal.” 58
A wealth of data supports poorer outcome in multiple anxiety disorders when there is a comorbid substance use problem.2,59 In anxious patients with bipolar illness, substance use is even more important a consideration in view of the high rate of substance use disorder comorbidity in bipolar patients and a similar association with poor outcome. A trial of abstinence will usually answer this question, although the duration has to be several months to evaluate the link between anxiety and use, there has to be ongoing treatment, preferably in a 12-step program (such programs have been shown to have anxiolytic effects themselves due to the support and empowerment they offer) and residual anxiety then has to be treated with either medication or CBT.
A number of studies have shown high rates of GAD comorbidity in adult patients with ADHD.60 It is not clear whether this is simply due to definitional overlap, with ADHD symptoms of restlessness and impatience being misattributed to GAD. This is a very tricky differential, since more refractory ADHD cases often suffer from comorbid anxiety.61 In these cases, use of guanfacine is sometimes preferable to stimulant treatment and may even mitigate adverse effects of the latter when used in combination. ADHD can also confuse evaluation of phobic avoidance, eg, a patient whose flying phobia seemed to be reactivated during several years of not being treated with stimulants, and who on close questioning revealed it is the aggravation and impatience related to the long waiting periods to get on a flight and the confinement during the long flight that was most problematic, rather than actual “anxiety.”