Pharmacotherapy of adjustment disorder: A review

Abstract

Background: Adjustment disorder has been reconceptualized as a trauma- and stressor-related condition, and there is a growing understanding of the psychobiology of stress responses. Against this context it is timely to review of the pharmacotherapy of adjustment disorder.

Methods: A comprehensive electronic database (Pubmed) was searched for randomised controlled trials of the pharmacotherapy of adjustment disorder. Data from each trial were extracted and collated.

Results: To date there have been relatively few controlled trials in this area. Comparator trials provide limited support for a number of antidepressant agents, and a series of studies indicate that etifoxine is superior to buspirone and benzodiazepines for adjustment disorder with anxiety.

Conclusions: The work done has been useful insofar as it provides clinicians with some insights into the advantages and disadvantages of a number of pharmacotherapy options. Additional rigorously designed trials are needed to further advance the field.

KEYWORDS:

• Adjustment disorder
• trauma- and stressor-related disorders
• pharmacotherapy

Previous papers in this special issue on adjustment disorder emphasise the prevalence and morbidity of this condition, its reconceptualization as a trauma- and stressor-related condition, and our growing understanding of the neurobiology of stress responses. This body of knowledge on adjustment disorder as a distinctive clinical entity (Horowitz 1986; Maercker et al. 2013; Strain and Friedman 2011) may well have implications for the pharmacotherapy of adjustment disorder, for example, suggesting new treatment targets.

At the same time, previous reviews indicate that there have been relatively few randomised controlled trials of pharmacotherapy for adjustment disorder (Arends et al. 2012; Carta et al. 2009; Casey 2014). Several factors may have contributed to this gap, including the conceptualisation of adjustment disorder as a residual or left-over diagnostic entity, and, relatedly, the difficulty in designing trials for a condition that is by definition self limiting.

This paper reviews previous work on the pharmacotherapy of adjustment disorder, before going on to discuss future directions for the field. By describing the existing evidence base I hope to contribute to work on the key question of whether understanding adjustment disorder as an independent entity closely related to other trauma- and stressor-related conditions entails a more productive conceptual framework for research on this condition in general (Horowitz, 1986; Laugharne et al. 2009), and for research on pharmacotherapy in particular.

Methods

The aim of this review is to tabulate and describe existing randomised controlled trials of the pharmacotherapy of adjustment disorder. Given the expectation that such a tabulation would include few placebo-controlled trials, that existing trials would employ different designs and outcome measures, the idea of a rigorous systematic review (along the lines of a Cochrane review) and meta-analysis was not entertained. I did, however, attempt a systematic approach in that (1) a comprehensive electronic database (Pubmed) was searched for randomised controlled trials of the pharmacotherapy of adjustment disorder using search terms that covered both the diagnosis and a range of psychotropic medications, with the most recent search run in May 2018, (2) reference lists of previous narrative reviews of adjustment disorder and of the treatment of adjustment disorder were also reviewed, and (3) the same data from each trial were extracted and collated (i.e. design, sample size, inclusion criteria, outcome measures, efficacy findings, adverse event (AE) findings).

Results

Randomized controlled trials of pharmacotherapy in adjustment disorder are listed in Table 1. Eleven trials have been published to date. These can be divided into placebo-controlled trials and comparator trials. Collated trials are detailed in the next two sections, after which methodological issues and clinical considerations are discussed.

Table 1. Randomized controlled trials of the pharmacotherapy of adjustment disorder.

Authors	Intervention	Sample	AD outcome
De Leo, (1989)	Viloxazine	n = 85	All arms equal
	vs lormetazepam
	vs S-adenosylmethionine
	vs psychotherapy
	vs placebo
Ansseau et al. (1996)	Tianeptine	n = 152	All arms equal
	vs alprazolam
	vs mianserin
Volz and Kieser (1997)	Kava-kava vs placebo	n =?	Unavailable
Bourin et al. (1997)	Euphytose vs placebo	n = 91	Euphytose > Placebo
Servant et al. (1998)	Etifoxine vs buspirone	n = 170	Etifoxine > Buspirone
Razavi et al. (1999)	Trazadone vs clorazepate	n = 18	Trazodone = Clorazepate
De Wit et al. (1999)	Trazodone vs clorazepate	n = 21	Trazodone= Clorazepate
Nguyen et al. (2006)	Etifoxine vs lorazepam	n = 191	Etifoxine = Lorazepam
Woelk et al. (2007)	Ginkgo biloba vs placebo	n = 25	Unavailable
Stein (2015)	Etifoxine vs alprazolam	n = 202	Etifoxine < alprazolam (wk 4), etofoxine > alprazolam (wk 5)
Syunyakov and Neznamov (2016)	Fabomotizole vs diazepam	n = 90/150	Fabomotizole > diazepam (in whole group)

Placebo-controlled trials

Early work on the pharmacotherapy of adjustment disorder not surprisingly focussed on agents that had been studied in depression and anxiety disorders, namely antidepressants and benzodiazepines.

A study by De Leo (1989) compared an antidepressant (viloxazine), a benzodiazepine (lormetazepam) and a neutraceutical (S-adenosylmethionine), with both psychoanalytically oriented supportive psychotherapy and placebo. Seventy patients were randomised, and the study lasted 4 weeks. The authors reported that none of the treatments had clearly superior effects over others, but also tentatively suggested that viloxazine, lormetazapam and S-adenosylmethionine had an advantage. The trial was, however, marred by a range of methodological flaws, including the lack of a double-blind design, the apparent absence of diagnostic criteria used for inclusion, the absence of a standardised measure of adjustment disorder symptoms and no systematic reporting of AEs.

Volz and Kieser (1997) compared kava-kava with placebo in the first multi-centre placebo-controlled study of the pharmacotherapy of adjustment disorder. One hundred and one patients who met DSM-III-R criteria for adjustment disorder with anxiety, generalised anxiety disorder, agoraphobia and specific phobia were recruited from general practices and randomised to kava-kava or placebo over 25 weeks. Kava-kava was superior to placebo on the main outcome measure, the Hamilton Anxiety Rating Scale, starting from 8 weeks on. Unfortunately the report of the trial does not detail the exact number of patients with adjustment disorder, nor the treatment response and AEs for this particular group of patients, markedly limiting the lessons that can validly be drawn from the data for research and practice related to this condition. The severe adverse hepatic events associated with kava-kava also bear consideration.

Bourin et al. (1997) studied euphytose, a combination of dry plant extracts of Pussifloru incurnutu, Valerianu oficinulis, Crutuegus oxyucunthu, Bulloru foetidu, Puulliniu cupunu and Colu nitidu, versus placebo. This product has been used in France for nearly a century for its anxiolytic effects. Euphytose appears to have a range of neurochemical effects, including binding to central benzodiazepine receptors. One hundred and eighty-two patients with adjustment disorder with anxious mood were recruited from general practices included in this 4-week study. Although a diagnostic algorithm was employed, the diagnostic criteria used are not specified. Euphytose was significantly superior to placebo on the Hamilton Anxiety Rating Scale, with an advantage already apparent at day 7, and was well tolerated.

Woelk et al. (2007) studied gingko biloba extract EGb 761, given reports that it was useful, not only for cognitive enhancement in cognitively impaired elderly subjects, but also for anxiety reduction in such patients. One hundred and seven patients with DSM-III-R generalised anxiety disorder and 25 patients with DSM-III-R adjustment disorder with anxious mood were randomised to two different doses of EGb 761 (240 and 480 mg/day) versus placebo for 4 weeks. On the primary outcome measure, the Hamilton Anxiety Rating Scale, both doses of EGb 761 were significantly more efficacious than placebo, and were well tolerated. However, sub-analyses in the small adjustment disorder group were not undertaken.

Comparator trials

A first comparative trial for adjustment disorder compared mianserin (an antidepressant, at 60 mg/day), alprazolam (a benzodiazepine, at 1.5 mg/day) and tianeptine (a psychotropic with both antidepressant and anxiolytic properties, at 37.5 mg/day) (Ansseau et al. 1996). One hundred and fifty-two patients with DSM-III-R adjustment disorder with mixed emotional features (anxiety and depression) were studied over 6 weeks. Similar improvement was seen on a range of anxiety and depression scales, including the Hamilton Anxiety Rating Scale, across all three treatment groups, and the interventions were equally well tolerated.

Razavi et al. (1999) compared trazodone (mean dose 111.5 mg/day) and clorazepate (mean dose 17.5 mg/day) in a small study of DSM-III-R adjustment disorder in patients undergoing treatment for breast cancer. Eighteen patients were enrolled in a 4-week study, with efficacy assessed by the Hospital Anxiety and Depression Scale and a number of other scales. A successful response to treatment was seen in 91% of those receiving trazodone and 57% of those receiving clorazepate, although in this small sample this difference did not reach statistical significance. There were also no group differences in adverse events. The authors concluded that trazodone is not associated with dependence and is therefore a valuable option in the treatment of adjustment disorders in cancer patients.

De Wit et al. (1999) also compared trazodone and clorazepate in a small study of DSM-III-R adjustment disorder in medical patients, those living with HIV. Twenty-one patients were enrolled in a 4-week study, with efficacy again assessed by the Hospital Anxiety and Depression Scale and several other scales. A successful response to treatment was seen in 80% of those receiving trazodone and 64% of those receiving clorazepate, and again in this small sample this difference did not reach statistical significance. There were also no group differences in adverse events. The authors again emphasised that trazodone is not associated with dependence and is therefore a valuable option in the treatment of adjustment disorders in people living with HIV.

A number of trials have compared the novel anxiolytic agent, etifoxine, with benzodiazepines. Servant et al. (1998) compared etifoxine with buspirone. One hundred and seventy patients with a DSM-IV diagnosis of adjustment disorder with anxiety were randomised to etifoxine (150–200 mg/day) or buspirone (15–20 mg/day). A non-inferiority analysis of the Hamilton Anxiety Rating Scale, indicated that the groups were not equivalent. Analysis of the global improvement score was significantly in favour of etifoxine starting from day 7. The efficacy index, which addresses both efficacy and tolerability, also favoured etifoxine.

Nguyen et al. (2006) compared etifoxine with lorazepam. One hundred and ninety-one outpatients with a DSM-IV diagnosis of adjustment disorder with anxiety were randomised to etifoxine (150 mg/day) or lorazepam (2 mg/day) for 4 weeks. On the main efficacy outcome measure, the Hamilton Anxiety Rating Scale (HAM-A), the effect of etifoxine was not inferior to that of lorazepam (54.6% vs 52.3% decrease, respectively). However, there was a greater number of responders (as defined by a 50% decrease in HAM-A) on etifoxine, and this drug was better tolerated, with fewer patients taking etifoxine experiencing a rebound in anxiety 1 week after drug discontinuation.

Stein (2015) compared etifoxine versus alprazolam. Two hundred and two outpatients with DSM-IV adjustment disorder with anxiety were randomised to etifoxine (150 mg/day) or alprazolam (1.5 mg/day) for 4 weeks. Etifoxine and alprazolam were accompanied by decreases in the main efficacy outcome measure, the HAM-A, with a difference between treatment groups of 1.78 in favour of alprazolam. However, after medication discontinuation, HAM-A scores continued to decrease in the etifoxine group, but increased in the alprazolam group; the difference between groups in mean change between days 28 and 35 was significant (p = .019). More treatment-related AEs were found in the alprazolam group, particularly central nervous system-related AEs, and especially after medication discontinuation.

Syunyakov and Neznamov (2016) compared fabomotizole with diazepam in generalised anxiety disorder. The article is written in Russian, the drug is not widely available outside of that country, and its mechanism of action is not well studied. Nevertheless, for the sake of completion, we note that the abstract of this article indicates that 60 patients with generalised anxiety disorder and 90 patients with adjustment disorder were included in this study. The abstract does not report findings for GAD and adjustment separately, but notes that reduction of anxiety on the primary outcome measure, the HAM-A, was significantly larger in the fabomotizole group, with a trend towards a better patient-rated score on the Sheehan Disability Scale. Further, there were fewer AEs in the fabomotizole group, with no afobazole withdrawal effects, and substantive diazepam withdrawal effects.

Methodological issues

As noted earlier, adjustment disorder is a condition that is time limited (although stressors may be ongoing, resulting in longer duration of symptoms). Study designs that have become standard in research on the pharmacotherapy of anxiety disorders, such as 12-week treatment studies, and 6-month placebo-controlled discontinuation studies, do not therefore seem appropriate. Furthermore, no antidepressant or anxiolytic has demonstrated superiority over placebo (although in one study there is evidence that a herbal agent does so). There is, therefore, a reliance on short-term studies (i.e. 4 weeks), and, increasingly, on comparative designs (and non-inferiority statistical analyses). Razavi et al. (1993) early on suggested a design that focussed on prevention of adjustment disorder using pharmacotherapy: this idea may well deserve further consideration. At the same time, a research programme focussed on stepped-care interventions for adjustment disorder may need to prioritise evaluation of potentially highly accessible and cost-effective interventions such as self-help web-based management.

Additional important methodological issues include those of incorporating optimal inclusion/exclusion criteria, as well as outcome measures. The MINI Neuropsychiatric Interview has the advantage of being able to assess a broad range of mood and anxiety disorders relatively quickly, and has been used to ensure that patients meet study criteria. The Hamilton Anxiety Rating Scale has been used as a primary outcome measure, even though it was not specifically developed to address the symptoms of adjustment disorder. More recently, a specific adjustment disorder scale has demonstrated potential value in a treatment outcome study (Bachem et al. 2016). Furthermore, recent investigations have provided useful information on key secondary outcome measures, such as the Sheehan Disability Scale (Stein, 2015; Syunyakov and Neznamov, 2016). The current review of the literature itself has important limitations (e.g. quality of studies was not rigorously assessed using a GRADE methodology), and given trial quality and heterogeneity meta-analysis of outcome measures across studies seems premature.

The reliance of the field on short-term studies and comparative designs, and the relative recency of work to develop a standardised symptom measure for adjustment disorder, makes it unlikely that any agent will be registered by the Food and Drug Administration or the European Medical Agency for adjustment disorder in the foreseeable future. There has been little attention in past treatment trials to the issue of comorbidity (including suicidal symptoms), other than as an exclusion criterion. There are no randomised controlled trials in adolescents or in the elderly, despite evidence for high prevalence and associated morbidity in these populations (Arbus et al. 2014; Ferrer and Kirchner 2015). There is also a need for further trials in key settings (e.g. consultation liaison psychiatry) and populations (e.g. first responders) (Fielden 2012; Strain et al. 1998). Controlled trials to date have been explanatory (rather than pragmatic real-world trials) (Thorpe et al. 2009), and there has been no work on combined pharmacotherapy plus psychotherapy. Future research that demonstrates the cost-efficacy of intervention may be particularly useful in making a case for adjustment disorder pharmacotherapy.

Clinical considerations

In the absence of a registered medication for the pharmacotherapy of adjustment disorder, it is important that the clinician adheres to the key principle of ‘primum non nocere’. Benzodiazepines are the most widely prescribed class of psychotropic agent (Stahl 2002); certainly, they have the key clinical advantage of causing an immediate subjective sense of anxiety reduction. At the same time, these agents are by no means a panacea; they are associated with a range of AEs, and once they have been prescribed continuously, discontinuation may be difficult to effect. Given the reconceptualization of adjustment disorder as a trauma- and stressor-related condition, it is worth emphasising that clinical guidelines invariably advise against the use of benzodiazepines for the prevention and treatment of posttraumatic stress disorder (Baldwin et al. 2014; Bandelow et al. 2012).

Other classes of medication should therefore certainly be considered as first line pharmacotherapy for adjustment disorder. A number of naturalistic studies have suggested that antidepressants may be particularly valuable in adjustment disorder (Galecki et al. 2005; Hameed et al. 2005), but these have not used a randomised controlled design, and so must be considered preliminary. Distinctions between adjustment disorder and depression may also give the clinician pause (Zimmerman et al. 2013). Some limited evidence also exists for nutritional and herbal agents, although it must be emphasised that not all of these agents are safe. Recent Cochrane reviews have argued nutritional and herbal supplementation appears effective and safe for anxiety and anxiety-related conditions (Miyasaka et al. 2006), but there are too few trials of passiflora and valerian to be certain about the role of these agents (Miyasaka et al. 2006; Miyasaka et al. 2007).

The etoxifine comparator studies have been useful in that they comprise well-controlled prospective studies in adjustment disorder with anxiety. Taken together, the data from this series of studies has been useful in demonstrating that etoxifine is superior to buspirone, and that, when compared to benzodiazepines, it has the important advantage of not being associated with medication withdrawal symptoms. Overall, therefore, when data from the discontinuation phase are considered, etifoxine appears superior to benzodiazepines in terms of both efficacy and tolerability measures. Recent data using a specific adjustment disorder measure, and using a range of secondary outcome measures, supports this conclusion (Bachem et al. 2016; Stein 2015). Further work is needed to determine whether this agent is also useful in adjustment disorders with depressive symptoms.

Conclusion

This paper has reviewed the limited literature on the pharmacotherapy of adjustment disorder, and discussed some of relevant methodological issues and clinical considerations. Given the paucity of relevant data, some may suggest the avoidance of medication, or the prioritisation of a psychotherapy approach. Certainly, an evolutionary perspective would emphasise that stress responses, even if distressing, are adaptive (Nesse and Stein 2012; Stein and Nesse 2011). At the same time, adjustment disorder is associated with considerable morbidity and even mortality, and the evidence base for non-medical interventions is also limited. Thus an individualised approach must be employed, with a plan made for each patient based on a rigorous clinical assessment, as well as a consideration of the literature as a whole (O’Keeffe and Ranjith 2007). An evidence base on pharmacotherapy of adjustment disorder has gradually emerged; placebo-controlled trials provide some support for the herbal agent euphytose, comparator trials provide limited support for a number of antidepressant agents, and taken together a series of studies indicate that etifoxine is superior to buspirone and benzodiazepines for adjustment disorder with anxiety.

This paper has also emphasised the point that conceptualisation of adjustment disorder as a trauma- and stressor-related condition invites a reconsideration of the pharmacotherapy of this condition. It is noteworthy, for example, that clinical guidelines caution against the use of benzodiazepines for posttraumatic stress disorder (Baldwin et al. 2014; Bandelow et al. 2012). Benzodiazepines have also been demonstrated to lead to withdrawal syndromes after brief treatments for adjustment disorder. There is preliminary evidence that etifoxine acts on neurocircuitry and neurochemistry that are relevant to posttraumatic psychopathology (Zeitler et al. 2016), but further investigation is needed to consolidate this point. Other agents, which more specifically target the neurocircuitry and neurochemistry related to trauma- and stressor-related pathology may ultimately prove particularly useful for the pharmacotherapy of adjustment disorder.

Statement of interest

In the past 3 years, Prof. Stein has received research grants and/or consultancy honoraria from Biocodex, Lundbeck, Servier, and Sun.

Acknowledgements

Prof Stein is supported by the South African Medical Research Council.