Can we add to the story? Perhaps by offering more clinical impressions. Our observations suggest that patients with narrowly defined melancholic depression (particularly when their depression is marked by psychomotor disturbance) are more likely to receive augmenting benefit. Patients with bipolar disorder also appear highly likely to respond. Thus, not only did some of our patients with established bipolar disorder describe "riding a high" out of their depression -- but several patients who had never previously responded did so following atypical initiation. Our patients did not always report this improvement, so clinicians may need to probe for this information. When a severely depressed patient improves rapidly, both the patient and the physician may judge it as a rapid return to an euthymic state and miss features indicative of a "high." In such patients, these "highs" are generally slight and transient, but can be dissected from abrupt euthymia. This might suggest that atypicals act on the putative "switch" mechanism.
In a refined observational study, I treated 10 consecutive patients with treatment-resistant melancholic depression with olanzapine(Drug information on olanzapine) augmentation and monitored improvement over the next week (Parker, 2002). Six patients showed rapid and substantive improvement over that brief interval. This study is informative in that daily ratings of mood, anxiety, insomnia and depression identified differential effects across those parameters. Thus, these six patients showed dramatic improvements in insomnia and anxiety, while their depression improved somewhat more slowly.
Such results raise the possibility that atypicals might be of benefit merely because they restore sleep, but most patients contemplating that possibility with me have generally rejected it on the basis that mood improvement occurs somewhat more slowly than sleep and anxiety benefits.
I began seeking views of other clinicians, expecting few to have tried such an augmentation strategy. The majority of clinicians I consulted also reported positive results using atypicalsas augmenting agents. It has now become quite rare for us to see a treatment-resistant patient at our tertiary referral service who has not been tried on an atypical antipsychotic prior to our assessment.
In the last decade there have been major advances in newer antidepressants. Each advance has emerged after careful evaluation involving controlled studies of large samples and up to a decade in investigation time. Following introduction of each drug, clinicians seek to understand their clinical effectiveness (as against their tested efficacy) and generally develop some gradual understanding about each drug's profile and, more important, the comparative benefits and situations where the drug might be recommended. This is obviously a slow process, respecting the scientific paradigm.
By contrast, the augmentation story overviewed here is extraordinary. We now have atypical antipsychotic drugs -- that lack an indication as either antidepressants or as antidepressant-augmenting drugs -- being widely used by psychiatrists when the published literature comprises only one controlled study and two case series.
Quo vadis? We need to be very cautious in using atypical antipsychotics as either antidepressant drugs (unsupported at the moment) or as augmenting antidepressant agents (the presumptive strategy) until clarification studies accrue. We need to establish that true augmentation occurs and is not merely a reflection of an anxiolytic phenomenon, or there is a risk that these antipsychotics may be used for patients who have a primary anxiety disorder, as occurred with the typical antipsychotic drugs in the past. Even if atypicals are beneficial, we must be aware of both immediate and long-term side effects, which must be respected in cost-benefit decisions. Since we do not know the long-term side effects of these drugs, great caution needs to be exerted, particularly when used on an ongoing basis. We need to establish whether there is an intra-class differential or whether there is a non-specific class augmentation benefit and if there is depression subtype specificity when we hypothesize that melancholic and bipolar depression is preferentially responsive.
My observations suggest that augmentation by an atypical requires a potentially effective antidepressant to be augmented, a situation generally not readily judged in advance. Thus, I have seen patients who failed to benefit from augmentation while receiving an SSRI or a selective norepinephrine(Drug information on norepinephrine) reuptake inhibitor but, when the antidepressant drug has been substituted with a TCA or an irreversible MAOI, have shown an almost immediate response. We need to establish if augmentation can be rapidly tapered or ceased in those patients who have returned to a euthymic state and, conversely, those situations that might determine a true need for an ongoing augmenting strategy. Finally and most important, we need to understand the biological rationale for such an augmentation phenomenon, as it may provide us with a greater understanding of the perturbations underpinning bipolar disorder and melancholic depression in particular.