ReviewPharmacological treatment of anxiety disorders: Current treatments and future directions☆
Highlights
► Incomplete treatment response is common and should be studied using novel methods. ► Neurogenesis-promoting drugs appear promising but are in early development. ► Drugs that enhance memory consolidation may augment exposure-based therapy, but long-term data are needed. ► Adjunctive use of psychedelic and narcotic drugs with psychotherapy has poor empirical support.
Introduction
Pharmacological treatments for anxiety disorders have become more tolerable, available, and numerous over the past half century. At the same time, research has yielded a vastly improved understanding of the neurobiological and physiological mechanisms involved in chronic anxiety and stress responses, suggesting new approaches to the treatment of anxiety disorders. Despite these impressive changes, however, between one-third and one-half of patients on a modern antidepressant do not achieve sustained remission from anxiety (Pollack, Otto, et al., 2008).
Why does this efficacy gap exist, and what should be the next step in treatment for these patients? Unfortunately, although patients often use antidepressant medications for years, high-quality data on the drugs’ long-term efficacy are limited. The problem is compounded by the growing number of different drug classes, which has prompted clinicians to combine drugs and change dosing regimens without good data on optimal treatment combinations. Billions of research dollars later, have we hit a wall in the development and application of pharmacological treatments for anxiety? What hope might there be for a genuine breakthrough treatment for treatment-refractory anxiety?
To evaluate these questions, we first review evidence for the safety, tolerability, and efficacy of first- and second-line drugs in the anxiety disorders. We discuss the strength of evidence for drug–drug and drug–psychotherapy combinations used as adjunctive or augmenting treatment approaches to treatment-refractory anxiety. In the remainder of this review, we evaluate potential innovations in the treatment of anxiety disorders, including novel molecular targets, memory-modulating drugs, and psychedelic and narcotic drugs. The results have largely been disappointing so far; in many cases, however, we identify concrete questions for future research, many of which may best be addressed through innovative research methods.
Section snippets
Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)
The widely studied SSRIs, and to a growing degree, the SNRIs (and for obsessive–compulsive disorder [OCD] the mixed noradrenergic and serotonergic reuptake inhibitor tricyclic clomipramine), are considered the first-line pharmacological treatments for anxiety disorders (see Ravindran & Stein, 2010, for a review). Specific phobia is the exception. In specific phobia, these medications have rarely been studied or used clinically because exposure therapy is considered the first-line treatment. The
Future directions in pharmacological targets
While much drug development is concerned with improving the efficacy and tolerability of existing anxiety medications (Nemeroff, 2003), considerable resources have been invested to identify novel molecular targets over the past decade (Miller, 2010). Recent research in this area has largely focused on drugs that act more selectively on specific subtypes of serotonergic receptors.
Pharmacological modulation of learning and memory
While the search for new drugs based on novel molecular targets has been faltering in recent years, preliminary human research into the use of memory-modulating drugs has been flourishing. The goal of this research is to develop drugs that enhance or disrupt specific learning or memory processes to improve outcome. The approach departs substantially from traditional psychopharmacology, which has primarily evaluated drugs that have more direct effects on anxiety and depression. Adjunctive memory
3,4-Methylenedioxymethamphetamine (MDMA) and cannabidiol
Although most psychedelic drugs have been illegal or heavily regulated in the U.S. and abroad for the past several decades, some researchers (e.g., Bouso et al., 2008, Doblin, 2002) have argued that psychedelic and other drugs may be able to augment exposure-based treatments for anxiety disorders (Bouso et al., 2008, Doblin, 2002). Indeed, correlational evidence links psychedelic substances to increased activation in the ventromedial prefrontal cortex (vmPFC) and to decreased amygdala
Discussion
Today, patients with anxiety disorders benefit from decades of psychopharmacological research that has yielded safer, more tolerable side-effect profiles than before – but without improved efficacy. As we have reviewed above, first-line antidepressants, such as the SSRIs and possibly the SNRIs, do a reasonable job of reducing anxiety, but they act slowly and often do not lead to sustained remission. Faced with incomplete response, clinicians and patients must decide how treatment should
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2022, Sleep Medicine ReviewsCitation Excerpt :SSRIs and SNRIs (e.g., clomipramine for OCD) inhibit the reuptake of serotonin or norepinephrine, respectively, thus augmenting serotonin synaptic levels [15]. They are deemed as first-line pharmacological treatments for most anxiety/anxiety-related disorders, although up to ∼30% of individuals may experience side effects and/or may be nonresponsive due to insufficient dose, poor adherence, treatment resistance, or inadequate treatment duration [15]. Of note, individuals who experience both GAD and MDD and undergo pharmacological treatment with SSRI (e.g., fluoxetine, venlafaxine) may experience disrupted sleep, particularly insomnia [111].
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This manuscript was supported in part by NIH grants R34MH087375 and R01MH066347. The authors thank Gerald Rosen for his excellent comments on earlier drafts of this manuscript.