Integrative Systematic Review on Pharmacological, Psychotherapeutic, and Neurostimulatory Treatment Options in Treatment-Resistant Anxiety Disorders.

INTRODUCTION

Treatment resistance in anxiety disorders (TR-ADs) constitutes a major clinical challenge conferring a considerable burden regarding quality of life and societal health costs.

METHODS

This systematic review provides an overview of pharmacological, psychotherapeutic, and neurostimulatory treatment options in adults with treatment-resistant generalized anxiety disorder (TR-GAD), panic disorder (TR-PD)/agoraphobia, and social anxiety disorder (TR-SAD).

RESULTS

A total of 26 randomized controlled trials (RCTs) and 36 open label studies were identified, with, however, mostly small sample sizes and several methodological limitations. According to RCTs, selective serotonin reuptake inhibitors (SSRIs) or clomipramine are effective in TR-PD after failure to respond to cognitive behavioral therapy (CBT). In pharmacological TR-SAD, switching from one SSRI to another or to venlafaxine was found helpful in open label trials. RCTs further suggest augmentation with quetiapine, risperidone, olanzapine, or pregabalin in TR-GAD, pindolol in TR-PD, and clonazepam in TR-SAD. Open label studies in TR-AD provide preliminary evidence for ketamine or augmentation with nefazodone, reboxetine, buspirone, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, divalproex sodium, levetiracetam, zonisamide, flumazenil, pregabalin, cannabidiol, and acamprosate. For pharmacological TR, CBT was effective in several RCTs. Following nonresponse to CBT, first evidence suggests effectiveness of Acceptance and Commitment Therapy and Mindfulness-Based Cognitive Therapy. Only inconclusive support was identified for repetitive transcranial magnetic stimulation in TR-AD.

CONCLUSION

In summary, this integrative review may provide an evidence base for expert recommendations, inform clinical guidelines, and inspire further research into innovative, personalized treatment of TR-AD increasing response rates and lowering the considerable individual and public health burden of anxiety disorders.