Pharmacotherapy for Anxiety Disorders: From First-Line Options to Treatment Resistance.

In this review, the author examines the evidence for psychopharmacologic treatments among adults for generalized anxiety disorder, panic disorder, and social anxiety disorder derived from clinical trials. For each disorder, major categories of drugs are reviewed, and then the evidence-based medications in each category are discussed. The author reviews key safety and tolerability considerations for each of the medications or classes. Evidence-based dosing for most specific agents is displayed in a comprehensive reference table. Subsequently, the author synthesizes the available information to suggest a pragmatic stepwise approach to treatment that accounts for patient-specific factors. To inform the guidance, the author incorporates and refines perspectives from treatment guidelines already written by clinical professional organizations. The author also briefly reviews the relatively new quantitative systematic review methodology of network meta-analysis (NMA) and discusses how NMA may help guide pharmacologic treatment sequencing decisions in the future by way of ranking treatments according to effect size and the relative amount of study to which treatments have been subject. Caveats of NMA studies are briefly discussed, as are results of recent NMAs regarding the pharmacologic treatment of anxiety disorders.

Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder.

BACKGROUND: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD. METHODS: A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions-Improvement scale of "much improved" or "very much improved." RESULTS: Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, -3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions-Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan. CONCLUSIONS: At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data.

Pharmacotherapy of anxiety disorders in the 21st century: A call for novel approaches.

While limited advances have occurred in the past 30 years in the pharmacological management of anxiety and stress-related disorders, novel molecular pathways both within and without the monoamine systems are currently under investigation and offer promising new avenues for more effective future treatments. Enhancing psychotherapy approaches with pharmacological compounds offers the potential to not only transform the standard of care of these conditions, but more broadly would introduce a paradigm shift in the way medications and their role in psychiatric care are conceptualised. Although further human trials and more translational research are sorely needed, continuing to pursue innovative mechanisms and treatments is hoped to yield substantial results in the coming decades and a departure from the reliance on chemical agents of the 20th century.