What are the pharmacotherapeutic options for adjustment disorder?

KEYWORDS:

• Adjustment disorder
• antidepressants
• anxiolytics
• benzodiazepines
• evidence-based medicine
• pharmacotherapy
• trauma- and stressor-related disorders

1. Introduction

Adjustment disorder (AD) is a common mental health condition that is characterized by the development of emotional and behavioral symptoms in response to an identifiable psychosocial stressor [1]. In hospital psychiatric consultation settings, AD may account for up to 50% of diagnoses, making it the most common diagnosis in this setting [1]. Younger age, higher education, female sex, and being single may increase the risk for AD [2,3]. AD has recently been reconceptualized as a trauma- and stressor-related condition, and appears alongside acute stress disorder (ASD) and post-traumatic stress disorder (PTSD) in the DSM-5 [1], ICD-10 [4], and ICD-11 [5]. This theoretical framework suggests that neurophysiological mechanisms underlying the stress response may provide useful treatment targets.

AD develops within 1–3 months after a psychosocial stressor and is characterized by distress that is disproportionate to the severity of the stressor. The stressor may be of any severity or type, in contrast to PTSD, which is triggered by exposure to life-threatening traumatic events. However, symptoms of adjustment disorder are characteristic of a trauma- and stressor-related disorder. Thus, it may be accompanied by preoccupations related to the stressor, excessive worrying, rumination, and recurrent or intrusive thoughts related to the stressor and its consequences [1]. DSM-5 lists a number of subtypes of AD, including those with depressed mood, those with anxiety, those with mixed anxiety and depressed mood, those with disturbance of conduct, those with mixed disturbance of emotions and conduct, and those with unspecified. Symptoms of AD are resolved within 6 months unless the stressor or its consequences persist.

Should the stressor resolve and symptoms persist beyond 6 months, then an alternate diagnosis such as an anxiety or mood disorder may be present. By definition, failure to adapt to the stressor results in impaired function across multiple domains, including social, occupational, educational, and other important areas. Thus, intervention is an important consideration, and a growing literature on both psychotherapy and pharmacotherapy has emerged [6,7]. However, there are considerable difficulties regarding study design due to the self-limiting nature of the disorder. Here, we review trials that have investigated the pharmacotherapy of AD (Table 1).

Table 1. Pharmacotherapy trials of adjustment disorder: Chronology of randomized controlled and comparator trials

Authors	Active agent	Control	Sample*	Length of study	Effect of medication
De Leo	Viloxazine	Lormetazepam	n = 85	4 weeks	No difference
(1989)	Viloxazine Viloxazine Viloxazine	S-adenosylmethionine Psychotherapy Placebo			No difference No difference No difference
Ansseau et al. (1996)	Tianeptine Tianeptine	Alprazolam Mianserin	n = 152	6 weeks	No difference No difference
Volz and Kieser (1997)	Kava-Kava	Placebo	Unclear	25 weeks	Unavailable
Bourin et al. (1997)	Euphytose	Placebo	n = 182	4 weeks	Favors euphytose
Servant et al. (1998)	Etifoxine	Buspirone	n = 170	4 weeks	Favors etifoxine
Razavi et al. (1999)	Trazodone	Clorazepate	n = 18	4 weeks	No difference
De Wit et al. (1999)	Trazodone	Clorazepate	n = 21	4 weeks	No difference
Nguyen et al. (2006)	Etifoxine	Lorazepam	n = 191	4 weeks	No difference
Woelk et al. (2007)	Ginkgo biloba	Placebo	n = 25	4 weeks	Unavailable
Stein (2015)	Etifoxine	Alprazolam	n = 202	4 weeks	Favors alprazolam at week 4, Favors etifoxine at week 5
Syunyakov and Neznamov (2016)	Fabomotizole	Diazepam	n = 90	4 weeks	Favors fabomotizole

* Sample includes participants with adjustment disorder only.

2. Placebo-controlled studies

Initial medication trials focused on agents typically used to treat depression and anxiety disorders. The first trial in adjustment disorder examined the effects of multiple agents [8]. In a 4-week trial (n = 85), De Leo compared an antidepressant with noradrenergic and serotonergic effects (viloxazine) to a benzodiazepine with GABAergic effects (lormetazepam), a neutraceutical with serotonergic effects (S-adenosylmethionine), and placebo. Psychoanalytic psychotherapy was also included as a comparator arm. None of the interventions had significant effects compared to placebo. There were also a number of methodological flaws, including lack of clear diagnostic criteria for inclusion, lack of standardized outcome measures, lack of double-blind study design, and lack of adequate reporting of adverse events.

The first multi-center, placebo-controlled trial for adjustment disorder compared kava-kava (a plant extract with GABAergic properties) to placebo over 25 weeks (n = 101). The study included patients with generalized anxiety disorder (GAD), agoraphobia, and specific phobia [9]. Although the study showed that kava-kava was superior to placebo on the Hamilton Anxiety Rating Scale from 8 weeks onwards, it is not clear how many participants had adjustment disorder, and the report does not delineate treatment responses for each condition. The authors also do not report on adverse effects, despite the potentially severe hepatic effects of kava-kava.

Bourin et al. studied euphytose, a combination of plant extracts that have been used in France for the treatment of anxiety [10]. It contains extracts from four plants with sedative effects (Ballota foetida, Crataegus oxyacantha, Passifloraincarnata, and Valeriana officinalis), and two with mild stimulant effects (Cola nitida and Paullinia cupana). The combined plant extracts appear to exert predominantly GABAergic effects through binding to benzodiazepine receptors. In a 4 week, placebo-controlled trial for adjustment disorder with anxiety (n = 182), euphytose showed significant effects on the Hamilton Anxiety Rating Scale starting at day 7 and was well tolerated [10]. Methodological limitations include the lack of clearly defined diagnostic criteria for adjustment disorder and the inclusion of only the anxious mood subtype.

The most recent placebo-controlled trial for adjustment disorder, conducted by Woelk et al. in 2007, compared Ginkgo biloba extract EGb 761 to placebo over 4 weeks (n = 25) [11]. The mechanism of action of this agent is unclear, but it is reported to have anxiolytic and cognition-enhancing properties. This study also included patients with GAD (n = 177), and while results were promising on the Hamilton Anxiety Rating Scale, subgroup analysis was not conducted, and therefore the specific effect for those with adjustment disorder is unclear.

3. Comparator trials

Ansseau et al. (1996) conducted the first comparator trial for adjustment disorder (n = 152), comparing a tetracyclic antidepressant with noradrenergic and serotonergic effects (mianserin), a benzodiazepine with GABAergic effects (alprazolam), and an atypical antidepressant with opioid agonist and glutamate modulatory effects (tianeptine) over 6 weeks [12]. Similar improvements were seen in all treatment groups, with no major differences in adverse effects.

Two studies compared trazodone (a sedative with serotonin antagonist and reuptake inhibitor effects) with clorazepate (a benzodiazepine with GABAergic effects) for the treatment of adjustment disorder [13,14]. One study (n = 18) showed potential benefit for trazodone (91% response rate) compared to clorazepate (57% response rate) at 4 weeks, however the difference was not statistically significant [13]. In a similarly small study (n = 21) conducted in patients living with HIV, trazodone showed similar efficacy compared to clorazepate (80% vs 64% response rate respectively), with fewer concerns of adverse effects [14].

A number of studies have compared the novel anxiolytic agent etifoxine to buspirone [15] and to benzodiazepines [16,17]. Etifoxine exerts its anxiolytic effects through dual action at the GABA receptor, via direct agonism and allosteric modulation, and may modulate neurocircuitry related to post-traumatic psychopathology [18]. Servant et al. found that etifoxine was superior to buspirone from day 7 (n = 170) in terms of efficacy and tolerability. Nguyen et al. found that etifoxine had a similar efficacy compared to the benzodiazepine lorazepam, without the undesirable rebound anxiety at 1 week post-cessation (n = 191). Finally, comparison with the benzodiazepine alprazolam, indicated that alprazolam showed greater initial benefit, but after cessation of drug the etifoxine group had continued improvement while the alprazolam group had rebound anxiety (n = 202).

The most recent comparator trial for pharmacotherapy with adjustment disorder compared fabomotizole with the benzodiazepine diazepam. Fabomotizole is another novel anxiolytic agent with GABAergic and other actions, including neurotrophic growth factor- and brain-derived neurotrophic factor-release-promoting actions, although its precise mechanism of action remains poorly defined. The trial included patients with GAD (n = 60) and adjustment disorder (n = 90) [19]. Although the data show promising effects with a reduction in disease severity of 72% in the fabomatizole group compared to 58% in the diazepam group and no withdrawal side effects for the fabomotizole group compared to 68% of the diazepam group, results for GAD and AD were not reported separately.

4. Expert opinion

Although AD is typically a self-limiting condition, it has a high prevalence and is associated with significant distress/impairment. It is therefore noteworthy that so few treatment trials of this condition have been undertaken. The reconceptualization of AD as trauma and stressor-related conditions suggests the possibility of targeting the stress response system with pharmacotherapy. While a number of anxiolytics have indeed been studied, there have been few placebo-controlled trials [6,7,20]. This may be due to the difficulties in study design for a condition that is self-limiting. In the absence of placebo-controlled trials, clinical recommendations must remain tentative.

Nevertheless, a number of lessons can be drawn from the existing database of pharmacotherapy trials. First, herbal products such as euphytose, kava-kava, and Ginkgo biloba have each showed some promising results in randomized placebo-controlled trials, although the studies often contain patients with other conditions, or have included patients with AD but without clearly defined diagnostic criteria applied for inclusion [9–11]. Although there are some concerns regarding liver damage from kava-kava, it is notable that euphytose extract may have GABAergic properties and appears safe. Given the ongoing relevance of the dictum ‘primum non nocere,’ this agent deserves consideration.

Second, there is concern about the use of benzodiazepines in a trauma- and stressor-related disorder for a number of reasons. Benzodiazepines have not shown efficacy in PTSD [21] and may even exacerbate risk for PTSD when used prophylactically [21]. Furthermore, risks include rebound anxiety on discontinuation. The antidepressants mianserin, tianeptine, and trazodone have not been shown to be more effective than a benzodiazepine [12–14]. Taken together, the current evidence base does not support the use of benzodiazepines for adjustment disorder, and further work is needed to substantiate the use of antidepressants in this condition.

Third, a number of studies have demonstrated that the anxiolytic etifoxine is more effective than buspirone and benzodiazepines, and is well tolerated [15–19]. This agent, which has GABAergic effects, therefore also deserves consideration in the clinical setting for adjustment disorder with anxiety. Further investigation of the role of the GABAergic system in AD may be useful, and further work using placebo-controlled trials is needed to make more definitive treatment recommendations. The novel anxiolytic fabomotizole has not been as well studied for adjustment disorder, but similarly deserves further attention given early promising results.

Developments in our understanding of the neurobiological underpinnings of the stress response may provide new targets for the treatment of adjustment disorder in the future. Studies targeting specific neurophysiological mechanisms involved with the stress response, and conducted in well-defined clinical populations, deserve to be undertaken. Anxiolytic agents such as etifoxine and fabomotizole, which seem to provide symptom relief without the unwanted adverse effects associated with benzodiazepines, may be of particular interest in such future work. Antidepressants may also prove useful in AD and might be chosen based on a range of factors including individual needs, and comorbidities [22]. There has been little work on combined pharmacotherapy and psychotherapy in AD, and this too deserves further attention.

Declaration of interest

Both authors are affiliated with the University of Cape Town. DJ Stein has received research grants and/or consultancy honoraria from Discovery Therapeutics, Johnson & Johnson, Lundbeck, Sanofi, Servier, Takeda and VistaGen Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This manuscript was not funded.