Anxiety disorders are a heterogeneous spectrum whose diagnostic criteria continue to evolve. With the DSM-5, anxiety disorders, trauma- and stressor-related disorders, and obsessive-compulsive and related disorders have been separated into a separate classification schema.
Among other changes, the DSM-5 also added a symptom cluster for “negative alterations in cognition and mood” to the criteria for post-traumatic stress disorder, separated agoraphobia from panic disorder criteria, changed the specifier option within social anxiety disorder, and defined several new disorders in the obsessive-compulsive subset.1
Similarly, there is increasing evidence for a broad spectrum of treatment responses, both to pharmacologic and non-pharmacologic modalities, across anxiety diagnoses. This diversity is evident when discussing antipsychotic efficacy. The list of anxiety diagnoses with demonstrated efficacy from antipsychotics is much narrower than the list of anxiety disorders showing benefit from selective serotonin reuptake inhibitors (SSRIs), for example.
The risks of metabolic side effects, as well as the sequelae of the dopamine blockade, can significantly impact morbidity and mortality, limiting the utility of antipsychotics. No antipsychotic has yet garnered an FDA indication for an anxiety disorder and the studies cited in the remainder of this article will focus on treatment of adults.
Cognitive-behavioral therapy (CBT) has robust, first-line evidence for treating obsessive-compulsive disorder (OCD).2 When pharmacology is employed, the usual first step is an SSRI. When OCD is refractory to an initial trial with an SSRI, the next step is still not augmentation with an antipsychotic. Clomipramine, for example, may beat SSRIs in monotherapy trials for OCD.3
Many clinicians, appropriately, try several monotherapy trials of different antidepressants before considering augmentation. Even if augmentation of an SSRI is ultimately considered, antipsychotics may not be the first choice, given evidence that augmentation with CBT is superior to augmentation with antipsychotics.4
That said, there are now meta-analyses that support eventual consideration of antipsychotic augmentation in algorithms for refractory OCD.5 The lack of head-to-head trials makes it difficult to come to a firm, evidence-based recommendation on which antipsychotic is the most efficacious. However, the risperidone studies, when grouped together, are particularly convincing.
Of the studies included in the Dold, et al meta-analysis, the two, placebo-controlled, risperidone augmentation trials that employed flexible dosing suggested efficacy at 2mg to 3mg per day.6,7 However, efficacy has also been seen with doses as low as 0.5mg per day.8 Compared to the many other treatment modalities that demonstrate benefit for OCD, risperidone conveys higher rates of, amongst other things, significant metabolic and dopamine blockade side effects. Certain dopamine blockade side effects, such as tardive dyskinesia, can be irreversible. These factors of comparative efficacy and side effects make risperidone less likely to be considered in OCD treatment algorithms.9
While antipsychotic studies of OCD most often employ a strategy of augmentation, trials of quetiapine for generalized anxiety disorder (GAD) have often been designed to study the medication as monotherapy. There have been enough trials of quetiapine monotherapy to enable the construction of meta-analyses that confirm the efficacy of the drug in GAD.10 However, quetiapine monotherapy does not appear to be more efficacious than SSRI monotherapy in head-to-head trials.11
There are also a number of other interventions with positive, placebo-controlled evidence for GAD. Venlafaxine and duloxetine both have FDA approval for GAD. The azapirones, of which buspirone is an example, have positive, placebo-controlled data.12 Though not FDA-approved for GAD, pregabalin has positive, placebo-controlled data.13
CBT can also be effective for GAD.14 Compared to many other interventions, quetiapine has a more significant side effect profile. Thus, despite the evidence of efficacy, quetiapine does not appear amongst the first choices of pharmacologic interventions in GAD treatment algorithms.15
Risperdal and olanzapine have been studied in post-traumatic stress disorder (PTSD), using DSM-IV diagnostic criteria. Some of these augmentation and monotherapy studies have demonstrated modest efficacy, though the results have been variable and meta-analyses have only been able to document a small effect size.16 The metabolic side effects, however, were evident.
However, there are studies where antipsychotics do not demonstrate efficacy over placebo.17 In light of the many other effective pharmacologic and psychological interventions for PTSD, the side effect profile of antipsychotics can be prohibitive. Antipsychotics are not first or second-line pharmacologic interventions for PTSD.9 Moreover, the overall data for antipsychotic efficacy, target PTSD symptom cluster, and target patient sub-population remains poorly defined.
Quetiapine does not appear to be effective for SAD.18 In the absence of co-occurring bipolar disorder, there have been no placebo-controlled trials of antipsychotics in panic disorder.
Though SSRIs are considered amongst the first-line pharmacologic options for OCD, GAD, SAD, PTSD, and panic disorder, the antipsychotics do not enjoy the same breadth of support. With varying degrees of evidence, antipsychotics do appear on treatment algorithms for several anxiety disorders, but not in the top tiers.
Ryan Kimmel, MD, is Assistant Professor in the Department of Psychiatry & Behavioral Sciences at the University of Washington School of Medicine.
- American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders : DSM-5 (5th ed.). 2013. Washington, D.C.: American Psychiatric Association.
- Foa EB, et al. “Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.” Am J Psychiatry. 2005; 162(1): 151-161.
- Greist JH, et al. “Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis.” Arch Gen Psychiatry. 2005; 52(1): 53-60.
- Simpson HB, et al. “Cognitive-behavioral therapy vs risperidone for augmenting serotonin reuptake inhibitors in obsessive-compulsive disorder: a randomized clinical trial.” JAMA Psychiatry. 2013; 70(11): 1190-1199.
- Dold M, et al. Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol. 2013; 16(3): 557-574.
- Hollander E, et al. “Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study.” Int J Neuropsychopharmacol. 2003; 6(4): 397-401.
- McDougle CJ, et al. “A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.” Arch Gen Psychiatry. 2000; 57(8): 794-801.
- Erzegovesi S. “Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study.” Eur Neuropsychopharmacol. 2005; 15(1): 69-74.
- Katzman MA, et al. “Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders”. BMC Psychiatry. 2014; 14 Suppl 1: S1.
- Maher, AR, et al. “Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis.” JAMA. 2011; 306(12): 1359-1369.
- Merideth C, et al. “Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study.” Int Clin Psychopharmacol. 2012; 27(1): 40-54.
- Chessick CA, et al. “Azapirones for generalized anxiety disorder.” Cochrane Database Syst Rev. 2006; (3): CD006115.
- Rickels K, et al. “Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.” Arch Gen Psychiatry. 2005; 62(9): 1022-1030.
- Cuijpers P, et al. “Psychological treatment of generalized anxiety disorder: a meta-analysis.” Clin Psychol Rev. 2014; 34(2): 130-140.
- Linden M, et al. “The best next drug in the course of generalized anxiety disorders: the “PN-GAD-algorithm”. Int J Psychiatry Clin Pract. 2013; 17(2): 78-89.
- Ahearn EP, et al. “A review of atypical antipsychotic medications for posttraumatic stress disorder.” Int Clin Psychopharmacol. 2011; 26(4): 193-200.
- Krystal JH, et al. “Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.” JAMA. 2011; 306(5): 493-502.
- Depping AM, et al. “Second-generation antipsychotics for anxiety disorders.” Cochrane Database Syst Rev. 2010; (12): CD008120.