Non‐pharmacological and pharmacological treatments act on the same brain

Treatment strategies for major psychiatric disorders, including affective and anxiety disorders, addictions and schizophrenia, include pharmacological and non-pharmacological interventions. These modalities might appear, at first glance, to have contrasting mechanisms of action, but their mechanisms may actually interact. Brain structure and function are altered by experience. Defined broadly, experience can include internal states that alter relevant neural pathways, external (including social) stimuli, or exposure to pharmacological agents. Pharmacological and non-pharmacological stimuli can have similar or interacting effects on behavior or brain plasticity. An example is cross-sensitization between rewarding pharmacological (including potentially addictive) stimuli and environmental stressors (1). Two psychotherapies, or two pharmacological treatments, may have complementary mechanisms of action. However, the fact that one treatment is pharmacological and the other non-pharmacological does not guarantee that they will have complementary mechanisms. Our challenge as clinicians is to determine how to use any potential treatment modalities available in the most efficient manner, especially given extensive evidence that response to single treatments is often suboptimal (2). Three kinds of stimuli that can influence the course of a psychiatric illness are the following: a) pharmacological treatment could correct imbalances that contribute to symptoms or relapse; b) external or social stimuli, including the structured stimuli provided by psychotherapies, could address the same, or different, imbalances; c) internally generated stimuli, including those resulting from the illness, and both specific and non-specific adaptations to it, could either ameliorate symptoms or make them worse. For example, episodes or exacerbations of depression, mania, anxiety or psychosis have natural histories in which, in general, they eventually resolve, though too often not before serious or tragic consequences have occurred (3). If mechanisms by which episodes eventually resolve could be identified, treatments could address them. These three classes of stimuli are likely to interact, and facilitating interactions among them can be an important aspect of successful treatment. A potential example is a pharmacological treatment which reduces susceptibility to anxiety, resulting in enhanced ability to participate in behavioral therapies aimed at broadening the individual's scope of activity. Thase et al (4) review extensive data from studies comparing combinations of pharmacological treatments with cognitive behavior therapy (CBT). In some ways these studies resemble pharmacological trials in which antidepressant or antimanic monotherapies are combined with placebo or a potential augmenter such as a second-generation antipsychotic. Potential problems in pharmacological and pharmacological plus non-pharmacological combination trials are similar. The first is choice of treatments. What is the rationale for the specific pharmacotherapy and psychotherapy that were chosen, and the evidence that the specific treatments involved actually have complementary mechanisms? “Psychotherapy” can have neurobiological targets (5), and “pharmacotherapy” can have behavioral targets (6). Most treatment augmentation strategies have not been based on mechanism, though there are notable exceptions, such as studies of augmentation by lithium of response to antidepressant agents, which were based on complementary effects on serotonergic function (7). Different classes of antidepressants can differentially affect brain function (8) and may therefore interact differentially with specific psychotherapies or clinical characteristics. The second problem is rational selection of patients for treatments, whether based on illness course, symptom pattern, genetics, family history, or other predictors. For example, in one study, a history of more than ten previous episodes was associated with relative lack of response to CBT (9), potentially consistent with an association between treatment non-response and a sensitized course of illness. Such individuals might have synergistic response to CBT combined with a pharmacological treatment that prevents expression of sensitized behavior (1). The third problem is that pharmacological augmentation studies can be confounded by under-treatment with the medication being augmented, biasing toward a positive effect of augmentation that may not be present if the original treatment were adequately dosed. Examples include studies in mania where lithium or valproate levels were suboptimal and there was no attempt to optimize them before addition of a second-generation antipsychotic (2). The same problem can occur in antidepressant-CBT trials, so choice of medicine and dose, or of type of psychotherapy, should be considered carefully. The fourth problem is that time courses of responses to treatment may differ, or effects of one treatment may enhance (or interfere with) effects of the other, depending on timing. Finally, the so-called placebo effect is considered a nemesis of treatment studies, whether pharmacological or not. However, in real life, the placebo effect is an important part of successful treatment, as it is a physiological effect that is integral to the therapeutic alliance (10). Every pharmacological treatment has a non-pharmacological component that cannot be dissociated from it. This alliance can be fostered, or inhibited, by strategies that are nominally pharmacological or non-pharmacological. While psychotherapy potentially involves more contact and opportunity for a therapeutic alliance to develop, so-called placebo effects are inherent in any treatment and cannot be dissociated from the effect of an “active” treatment (11). Selecting and administering a treatment in a manner that fosters adaptation and resilience is likely to increase its effectiveness as well as that of concomitant treatments.