Off-label Use of Valproate in Anxiety Disorders
Formation continue & perfectionnement Pharmacologie et toxicologie cliniques Psychiatrie et psychothérapie
Use beyond Approval

Off-label Use of Valproate in Anxiety Disorders

Issues
Formation continue & perfectionnement Pharmacologie et toxicologie cliniques Psychiatrie et psychothérapie
Calogero Crapanzano<sup>a</sup>
Calogero Crapanzanoa
Autres auteurs
Ilaria Casolarob, Chiara Amendolac, Andrea Politanod
Édition
2024/08
DOI:
https://doi.org/10.4414/sanp.2024.1362827258
Swiss Arch Neurol Psychiatr Psychother. 2024;175:1362827258
Affiliations
a ASPAG, CSM Licata, Licata, Italy
b Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Milano, Italy
c Azienda USL Toscana Centro, CSM Scandicci, Firenze, Italy
d Clinica S. Croce, Orselina, Switzerland

Publié le 15.08.2024

Abstract

Some evidence from preclinical and clinical studies suggests that valproate may have therapeutic effects in the treatment of anxiety disorders. We reviewed the existing literature on the efficacy of valproate in the treatment of these psychiatric disorders.
Keywords: Anxiety disorders; Biological psychiatry; off-label; Psychopharmacology; Treatment resistance
Anxiety disorders represent the most common category among mental illnesses, with a lifetime prevalence of approximately 31% in the United States of America. However, only 60–85% of patients show an adequate clinical response to pharmaco-psychotherapy, with only about 50% achieving a full recovery [1]. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are considered the mainstays of evidence-based pharmacological treatment for anxiety disorders, with efficacy rates ranging from 50 to 60%. For non-responders, several strategies are suggested, including increasing maximum tolerated doses, switching to other first-line standard treatments, and using pharmacological and psychotherapeutic combinations. Even so, alternative medication treatments for anxiety disorders, such as monotherapy or augmenting agents, remain promising. Glutamatergic transmission has been linked to anxiety disorders, and anticonvulsants that modulate and restore homeostasis between glutamate and GABA have been studied as potential novel treatments [1, 2].
In this work, we reviewed the current evidence for pharmacotherapies involving valproate in anxiety disorders. A comprehensive search on PubMed from inception to October 2023, using the search input “(valproic or valproate or divalproex) AND (anxiety)”, retrieved 1476 results. Criteria for inclusion were the following: anxiety disorder diagnosis, age ≥18 years, valproate as the intervention, none, placebo, or other active treatments as comparators, and quantitative or qualitative evaluation of overall or specific symptoms of anxiety. We implied no restrictions for study design. We excluded studies that reported patients with psychiatric comorbidities and studies published in a language other than English. Furthermore, the reference list of each relevant study was checked for additional information. Seven studies were included: two open-label studies and one randomized controlled trial (RCT) on Panic Disorder, one RCT and one case report on Generalized Anxiety Disorder, and two open-label studies on Social Anxiety Disorder (table 1) [3–9]. All but two studies used clinician-rated scales for the assessment of anxiety [7, 8]. Valproate was found to be effective in all considered studies except one [8], and the dosage was generally consistent. The most common side effects reported were sedation, nausea, and dizziness.
The existing literature, although scant and dated, supports the efficacy of valproate in ameliorating anxiety symptoms as well as its general safety. The anxiolytic properties of valproate have been widely reported in rodent tests, translational human models of anxiety behavior, and investigations involving experimentally induced panic attacks. These effects may be mediated by: i) blocking voltage-dependent sodium and T-type calcium channels; ii) strong GABAergic potency due to direct action at GABA-B receptors, causing an increase in brain GABA; and iii) inhibiting the GABA-degrading enzyme GABA transaminase [10–12]. Of interest, valproate, rather than lithium, appears to have a better response in the presence of a comorbidity of bipolar and anxiety symptoms/disorders [13]. Since anxiety disorders can precede the onset of a mood disorder and anxiety is one of the most important predictors of a new-onset bipolar spectrum [14], this could explain why patients with subthreshold hypomanic symptoms and anxiety disorders may respond to valproate. However, there is currently no evidence to support the use of valproate as a first-line treatment because studies rely primarily on open-label trials. Valproate, as a monotherapy or augmenting agent, should be reserved for cases where previous and evidence-based treatments have failed to achieve a satisfactory clinical response. Further research is needed to establish the potential efficacy of valproate in anxiety disorders and the most responsive clinical phenotypes.
Calogero Crapanzano ASPAG, CSM Licata, Italy
Calogero Crapanzano
Department of Mental Health
ASP 1 Agrigento
Azienda Sanitaria Provinciale di Agrigento
San Giacomo D'Altopasso,
92027 Licata
Italy
calogerocrapanzano87[at]gmail.com
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Funding Statement
The research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Conflict of Interest Statement
The authors have no potential conflict of interest to declare.
Author Contributions
All authors have contributed equally to this work and approved the final version.

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