The Stimulants effectiveness in depression disorders
The latest results of the research study indicate that stimulants are effective in improving depression symptom severity when compared with placebo. Several systematic reviews of atypical antipsychotics in adults with MDD have been published, providing an opportunity to benchmark and provide preliminary evidence of relative efficacy of stimulants. For example, the estimated efficacy of adjunctive atypicals (ie, aripiprazole, olanzapine, risperidone, and quetiapine) in MDD (ie, response rate of 1.64) 34 compares favourably with the results reported herein.
It is additionally noted that atypical antipsychotic efficacy in MDD is greater as a function of number of prior failed treatments. It is unknown, however, whether the efficacy of psychostimulants varies as a function of prior antidepressant history. We were also unable to determine whether the efficacy of stimulants in MDD differs across a particular set of symptoms, “clusters/factors,” or along particular dimensions/domains.
The determination of stimulant efficacy in adults with mood disorders may be informed by fundamentally altering the conceptual framework wherein they are studied. The efficacy of all psychotropic agents is not delimited to the diagnostic categories defined in the Diagnostic and Statistical Manual of Mental Disorders. As opposed to the traditional model of efficacy (with its inherent assumptions) that a psychostimulant would offer “broad-spectrum” efficacy, the pharmacodynamic profile of psychostimulants may indicate that they are more domain/dimension specific.
The pharmacodynamic profile of psychostimulants provides rationale for study in mitigating cognitive-emotional and neurovegetative disturbances in individuals with mood disorders. In support of this hypothesis, a single, randomized, placebocontrolled trial indicates that lisdexamfetamine is superior to placebo at improving measures of executive function in adults with MDD. Moreover, a post hoc analysis of a negative trial employing osmotic release oral system methylphenidate indicated that the psychostimulant was superior to placebo on measures of anhedonia.6 Available evidence also indicates that conventional antidepressants have differential efficacy across the dimensions/ domains of mood disorders. For example, results from a recently published meta-analysis by our group indicate that there are significant differences between conventional antidepressants in subdomains of cognitive function. Although beyond the scope of this paper, the foregoing collection of observations provides an empirical basis for a viable and testable hypothesis that perhaps psychostimulants may offer clinically relevant benefits in some domains of psychopathology encountered in MDD and other brain-based illnesses.
There is a risk that stimulants may destabilize adults with BD. Notwithstanding, there is a dearth of evidence supporting or refuting the assertion that psychostimulants destabilize individuals with BD at a rate higher than would be expected with placebo. It should, however, be additionally noted that, until sufficiently powered studies are conducted, firm conclusions regarding their safety and efficacy cannot be established.
There are significant methodological limitations with the studies included in the analysis that limit the interpretations and inferences of the meta-analytic findings. For example, the patient composition was not only heterogeneous with regards to having either MDD or BD but also included individuals who were eligible on the basis of having substance use disorders or concurrent medical disorders (eg, traumatic brain injury, cancer, attention-deficit/hyperactivity disorder). The foregoing limitation could also be interpreted as a strength (ie, ecological validity of the sample). Another limitation of the study includes the challenge of successful blinding in clinical trials because of the immediate and potentially unblinding effects of stimulant medications. Moreover, the small sample sizes of many of the studies reviewed increase the risk for an overestimation of the treatment effect. This has been well described and represents a significant limitation of the existing studies of stimulants.
Other sources of heterogeneity were sample size, age of subjects, number of sites involved in studies, duration of trial, diagnoses, and dosing of psychostimulant employed. The heterogeneity in diagnosis is a critical limitation herein, because available evidence indicates that MDD and bipolar I/II disorders are heterogeneous syndromes with differential response, tolerability, and safety characteristics in the context of interventional studies. For example, it could be reasonably surmised that the risk of mood destabilization and/or hypomanic switch with psychostimulants and/or propensity for misuse may be differentially expressed in the bipolar population when compared with the unipolar population. Notwithstanding the foregoing limitation, we decided to include both bipolar I/II disorder and MDD populations because our principle aim was to look at the totality of available evidence and not make any specific claims in any particular patient subpopulation.
The heterogeneity in the type and formulation psychostimulant employed is particularly noteworthy, insofar as within the psychostimulant category, there are significant pharmacokinetic differences. Although nondopaminergic stimulants (eg, modafinil) share similar pharmacodynamic targets with conventional stimulants, they cannot be assumed as being identical in their pharmacological activities. In addition, most trials employed the “add-on” design, whereas relatively few employed the monotherapy design.
Moreover, studies were mixed with respect to requiring either prospective/historical antidepressant failure, whereas others employed a traditional add-on design, that is, administration after failure on index antidepressant, and others used a combination design, that is, coprescription of psychostimulant and antidepressant versus antidepressant monotherapy, at study baseline. Relatively few studies employed the monotherapy treatment design. In addition, results of the Harbord test as well as the funnel plots are suggestive of publication bias, warranting future research inclusive of unpublished data.
Our results suggest that psychostimulants may be capable of reducing overall depressive symptom severity in adults with mood disorders. Because of the surfeit of limitations that exist, a strong conclusion about efficacy being established cannot be made. Notwithstanding, our interpretation of the extant studies is that results are directionally consistent with the possibility that some degree of symptom mitigation may be expected. The available studies are less hypothesis confirming and more hypothesis generating. For example, a hypothesis that is derived from the available evidence is that psychostimulants may benefit dimensions of psychopathology in MDD (eg, cognitive functions). Remarkably, “target-engagement” studies, wherein psychostimulant engagement of neural structures implicated in MDD, have not, to our knowledge, been published.