Stimulants for depression: On the up and up?

Abstract

The use of traditional psychostimulants (methylphenidate and dexamphetamine) and stimulant-like drugs (modafinil and armodafinil) for the treatment of depression is a growing concern given the lack of research evidence supporting their effectiveness. The current article describes the role of stimulants in treating depression – specifically their risks and benefits and their potential use alongside antidepressants. Clinically, the rapid amelioration of depressive symptoms with traditional psychostimulants is often dramatic but short-lived, and this suggests that they likely operate via different mechanisms to conventional antidepressants. More importantly, there is little evidence from randomised controlled trials supporting their efficacy in treating depression, although modafinil has been shown to be effective in reducing prominent depressive symptoms, such as fatigue. Research is urgently required to clarify psychostimulants’ mechanisms of action and to evaluate their long-term benefits and risks in the treatment of major and bipolar depression. Ultimately, specificity of action needs to be determined to inform the sophisticated clinical use of psychostimulants in the management of depression. Until then they should only be prescribed if absolutely necessary, and even then their prescription should be facilitatory and time limited unless it is for investigational purposes.

The treatment of depression remains unsatisfactory, partly because of difficulty in clinically defining and diagnosing depression, but also because our real-world treatment approaches are less than ideal. For instance, beyond the first few steps of treatment (Malhi et al., 2015a), subsequent therapeutic strategies to manage poorly responding depression lack a substantive evidence base. Therefore, when antidepressants fail to achieve sustained recovery, doctors have no choice but to draw on their clinical experience, and adopt a heuristic approach. Thus, once evidence-based therapies have been exhausted, less robust empirically validated measures are sometimes trialled (Malhi et al., 2016). Historically, this is where psychostimulants have been administered, somewhat experimentally, and usually for the treatment of severe refractory depression. Prior to the introduction of antidepressants, psychostimulants provided a treatment option that appeared to produce significant improvement in mood (i.e. inducing euphoria and increasing motor activity) (Orr and Taylor, 2007). Even though a broad range of antidepressants are now available, the use of psychostimulants for the treatment of depression continues to the present day. This is cause for concern, because the effectiveness of psychostimulants in mainstream clinical settings lacks sufficient evidence.

In this article, we briefly consider the role of stimulants in the treatment of depression, the risks associated with their use, and how they may potentially be used alongside antidepressants.

Introduced initially in the 1930s, psychostimulants are a heterogeneous group of agents that have been used for a broad range of indications, including achieving weight loss and cognitive enhancement, and treating a variety of medical and psychiatric conditions ranging from asthma to attention deficit hyperactivity disorder (ADHD). Within this ‘class’, the classic psychostimulants are methylphenidate and dexamphetamine, while other agents are usually described as having ‘stimulant-like properties’. For example, modafinil, which promotes wakefulness and is marketed for the treatment of fatigue, narcolepsy and other sleep disorders, is unlike classic psychostimulants because its chemical actions likely involve modulation of glutamate, γ-aminobutyric acid (GABA), histamine and hypocretin activity rather than accentuating monoamine neurotransmission (Corp et al., 2014).

It is important to note that amphetamine comprises two enantiomers of which dexamphetamine is the more active. This should not be confused with methamphetamine (methylated form of amphetamine), which also has some medical indications, but is mainly abused as a recreational drug. Methamphetamine also has two enantiomers and again dextromethamphetamine is the more potent form.

Classic psychostimulants (methylphenidate and lisdexamphetamine)

Proponents for the use of classic psychostimulants as ‘antidepressants’ in the treatment of depression often point to the rapid symptomatic improvement that accompanies their administration – specifically, increased alertness, energy and drive, and a return of cognitive function (Madhoo et al., 2014). These changes are usually noticeable within days and the timing and degree of seeming improvement raises some interesting questions. First, how do psychostimulants achieve these pronounced effects and especially with such rapidity? Second, are these clinical effects contingent upon whether psychostimulants are administered alongside antidepressants? In other words, is there an interaction between antidepressants and psychostimulants and, if so, what is the nature of this? Currently, there are no satisfactory answers to these questions, but the rapid onset of action indicates that psychostimulants may differ pharmacologically from conventional antidepressants in terms of their primary action. In practice, psychostimulants typically produce discernible clinical effects within days, while antidepressants act over a much longer timeframe. With conventional antidepressants a response typically emerges after 3 weeks of optimal treatment and sustained improvement only occurs after 6–8 weeks of sustained therapy (Malhi and Byrow, 2016; Malhi et al., 2015a). This is because the effects of antidepressants are the result of significant underlying neurobiological changes that produce and maintain clinical improvement and eventually lead to functional recovery. Results from a recent study that compared treatment response across depressed groups prescribed citalopram + placebo, methylphenidate + placebo or citalopram + methylphenidate, corroborate clinical experience. The effects of methylphenidate occurred during the first 4 weeks of administration, whereas sustained symptomatic improvement reflecting most likely the effects of citalopram only became apparent from week 4 to the end of the study (week 16) (Lavretsky et al., 2015; Nelson, 2015). Notably, an accelerated rate of response did not translate to significantly higher rates of remission with combination therapy compared to citalopram monotherapy, suggesting that psychostimulants do not augment the actions of antidepressants but instead perhaps act in a ‘facilitatory role’, in which their short-lived symptomatic effects prime the subsequent more sustained effects of antidepressants. The temporal difference between the effects of antidepressants and psychostimulants suggests that these arise via separate mechanisms of action.

Predictably, the side effect profile of classic psychostimulants is also different from that of conventional antidepressants. But interestingly, despite the increased potential for addiction and other adverse events associated with classic psychostimulants use, findings from randomised controlled trials (RCTs) suggest they are relatively well tolerated, at least for short periods of time such as up to 9 weeks (Abbasowa et al., 2013). Rates of adverse events occurring over longer periods are scarcely reported in the literature because the majority of psychostimulant studies in depressed patients are of relatively short duration and have not examined the long-term effects of these agents (Abbasowa et al., 2013; Orr and Taylor, 2007) – with the exception of one study which followed patients for 16 weeks (Lavretsky et al., 2015). However, even 16 weeks is insufficient given that depressive disorders are chronic lifelong illnesses. Until there has been proper investigation of the long-term effects of traditional psychostimulants on patients with depression, it is difficult to reach definitive conclusions regarding their safety and tolerability.

In a similar vein, high-level evidence (e.g. randomized controlled trials: RCTs) elucidating the effectiveness of traditional psychostimulants in treating depression is relatively scarce. Even methylphenidate and dexamphetamine have at best a modest evidence-base. For example, to date, only a handful of RCTs have examined the augmentation of antidepressants with psychostimulants and two of these failed to demonstrate any meaningful benefit (Patkar et al., 2006; Ravindran et al., 2008), while a preliminary report examining the effect of lisdexamphetamine (a prodrug of dexamphetamine) only managed a modest effect by lowering the statistical threshold (Trivedi et al., 2013). Thus, a recent review concludes that ‘no explicit evidence for the effectiveness of these agents in the therapeutic management of depression was retrieved’ (Abbasowa et al., 2013: 380). The evidence is even sparser for the treatment of bipolar depression, where, to our knowledge, only one RCT has examined the effects of lisdexamfetamine as an adjunctive treatment for bipolar depression, and again there was no significant effect on the primary outcome measure (Montgomery-Asberg Depression Scale). However, there were significant effects on secondary measures of depression such as sleepiness, fatigue and binge eating (McElroy et al., 2015).

It is also important to bear in mind that psychostimulants can theoretically cause a treatment emergent affective switch (TEAS) into mania – especially in those patients that have bipolar disorder (Malhi et al., 2015b). Thus, classic psychostimulants should be avoided as they can precipitate a TEAS. However, in practice, this is relatively uncommon (El-Mallakh, 2000) and McElroy et al. (2015) reported no occurrences of (hypo)mania in 11 participants receiving lisdexamfetamine.

Given the range of antidepressants available for the treatment of depression and the existing strategies of augmentation and combination, it is interesting to speculate as to why the off-label use of psychostimulants occurs despite a dearth of evidence supporting their efficacy. We proffer three possible causes. First, is the expediency of ‘response’, which confers face validity and implies potency. Second, feelings of euphoria and increased activity, albeit transient, are rewarding and offer immediate relief for the patient – and naturally this increases treatment acceptance. Finally, it may be a consequence of the similar use of benzodiazepines and atypical antipsychotics to manage antidepressant initiation associated anxiety. Clinically, such facilitation has proven to be a useful strategy, provided the ‘facilitating agent’ is promptly withdrawn once antidepressant treatment has been successfully established. Thus, a similar argument could be extended to the use of stimulants as facilitating agents in conjunction with antidepressants and it may be that clinicians have emulated this strategy with off-label use of stimulants. However, it is important to emphasize that even with benzodiazepines and atypical antipsychotics their use must be time limited, otherwise ongoing treatment runs the risk of resulting in dependence and serious adverse effects.

The concept of a facilitating agent suggests that there may not be a need for the continued administration of psychostimulants over the entire course of treatment, as is often the case with the majority of research studies examining the combination of psychostimulants with antidepressants. This is subtly different from adjunctive treatment per se, where the effects of the secondary agent amplify the effect of the primary antidepressant and may also have a synergistic effect via a complementary mechanism of action (such as the co-prescribing of two antihypertensives with differing modes of action) – hence necessitating ongoing co-administration. Research studies have yet to compare these different approaches and the evidence to date suggests that, overall, psychostimulants are not an effective stand-alone treatment strategy for depression. Consequently, treatment guidelines do not advocate the use of traditional psychostimulants in the treatment of depression (Carvalho et al., 2014; Malhi et al., 2015a). However, it is evident that further research investigating the ‘off-label’ use of stimulants is necessary to determine their efficacy and best approach to administration.

Stimulant-like agents (modafinil and armodafinil)

Modafinil and armodafinil (R-en-antiomer of modafinil) are considered ‘stimulant-like’ agents and are different to the classic psychostimulants discussed thus far, in terms of the associated mechanism of action, risks, and extant research evidence. In comparison to the more traditional psychostimulants, the risks relevant to treatment using the stimulant-like drug modafinil, have been more extensively examined and show that this treatment is generally well tolerated and safe (Goss et al., 2013). There have, however, been incidents of adverse events such as increases in suicidal ideation (Dunlop et al., 2007) as well as reports of increased symptoms of (hypo)mania/switching (Calabrese et al., 2010). Thus, although, modafinil has the added advantage of better tolerability and less potential for abuse and addiction compared to traditional psychostimulants, its use as an antidepressant remains controversial and ‘off-label’.

Furthermore, many more RCTs have investigated the effects of modafinil on depressive symptoms than have investigated conventional psychostimulants. Findings suggest that adjunctive modafinil may reduce depressive symptoms more than selective serotonin re-uptake inhibitor (SSRI) monotherapy (Corp et al., 2014; Goss et al., 2013), but findings are not uniformly positive (e.g. Dunlop et al., 2007; Fava et al., 2005), and, importantly, these studies have often used samples enriched in terms of symptoms of sleepiness and fatigue. In some studies depressed patients have shown overall clinical improvement measured by the Clinical Global Impressions-Improvement scale (Fava et al., 2005). Other reviews have emphatically concluded that there is a need for higher quality evidence derived from RCTs before modafinil can be used to treat depression in routine care (Abbasowa et al., 2013; Connolly and Thase, 2011). Thus, although it seems that adjunctive treatment with modafinil may be useful in treating specific symptoms of depression, such as fatigue, further investigation into its optimal use is necessary.

Since publication of the review by Corp et al. (2014), the effectiveness of adjunctive armodafinil treatment has been examined in bipolar depressed samples. These studies have yielded conflicting findings, with some (Frye et al., 2015; Ketter et al., 2015) concluding no improvements in primary outcome measures compared to placebo, and another providing evidence of a significant improvement in the same primary outcome measure (Calabrese et al., 2014). The effect size reported by Calabrese and colleagues, however, was small (0.28), and the study has been criticized for being underpowered (Ostacher, 2014). Clearly, these findings need to be replicated and corroborated before firm recommendations can be made as regards the treatment of bipolar depression using armodafinil.

Conclusion

The continued clinical use of stimulants for the treatment of depression reflects in part the desperation that both clinicians and patients feel when faced with this illness, especially when conventional therapies fail or produce only a partial response. In practice, psychostimulants are inherently ‘satisfying’ to prescribe because patients experience almost immediate benefits and clinicians observe this clinical improvement in their patients. This is understandably gratifying for all those involved, and even though the effects are usually short-lived the positive responses reinforce the future use of psychostimulants. However, the dearth of research supporting the use of psychostimulants in the treatment of depression means that clinicians have to make difficult treatment decisions based on clinical experience alone and this burdens them with unnecessary additional risk.

Hence, though the clinical use of stimulants appears to be on the up and up, it is not evidence-based, and rigorous investigation is needed before they can be used as mainstream treatments for the management of depression.