In sequential treatment, subsequent antidepressant medications commonly are selected based upon their putative mechanism of action (MOA), with medications that have a different MOA usually given preference.17
It has never been shown, however, that MOA is related to effectiveness in switching or combining medications.18
The results from level II treatment in STAR*D suggested that patients respond or remit to different antidepressants at similar rates, regardless of the MOA.19-20
The sole reliable predictor of improvement in sequential treatment is that improvement at one step is associated with further improvement at the next step, whereas failure to improve indicates a poor prognosis for improvement during future treatments.19,21
The STAR*D study demonstrated that each subsequent medication trial was less and less likely to be effective for patients with unsatisfactory response at the previous level.13,19,21-23
The development of increasing resistance over the course of antidepressant treatment is well established but not well understood. It largely has been interpreted as representing the fact that those who fail to benefit from adequate trials of earlier treatments are simply predisposed not to respond to multiple treatments, sometimes because of comorbid conditions.24
This hypothesized process through which successive treatment failures identify and isolate an increasingly treatmentresistant population may account, at least in part, for the escalation in failure rates with successive trials. This “distillation” hypothesis, however, is unlikely to account fully for increasing treatment resistance with multiple antidepressant trials. Even within a trial of a single antidepressant medication, there is a great deal of heterogeneity in onset of improvement that is not easily explained by commonly measured clinical features. Half of patients require more than 6 weeks to enter remission and a significant number of patients still enter remission up to 12 weeks, yet these later remitters eventually may attain a degree of improvement comparable to those who enter remission rapidly.5
A number of factors are likely to affect speed and completeness of medication responsiveness. Whereas some of these factors may reflect heritable or constant biological factors, others may be more dynamic and represent the state of the individual at the specific time that he or she enters treatment.25-27
Many such intraindividual factors are psychological, including patient expectations, cognitions, or conditioned responses. Data from subjects enrolled in clinical trials has shown that patients with high expectations of the effectiveness of their treatment are more likely to benefit from their treatment,28,29
and to respond more rapidly.29
Patients who are uncertain about the benefit of their antidepressant treatment may even discontinue medication before it has had time to work.30
These findings are consistent with the fact that in the setting of a placebo controlled trial, patients* certainty that they will be receiving the active medication as compared with placebo is directly related to their likelihood of response. Patients who are informed that they have a 50% likelihood of receiving active medication are significantly more likely to respond than those who are informed that their probability of receiving medication is only 20%. 31
It is reasonable to postulate that anything in the treatment setting that alters patients' expectations of improvement is likely to alter their likelihood of benefiting from a medication. Insofar as prolonged prior administration of an ineffective antidepressant may diminish expectations of improvement, this practice may contribute to the failure of subsequent trials.
Cognitive theories of depression suggest that, in the context of dysfunctional attitudes that subserve depression, failed treatment attempts would perpetuate negative thoughts and contribute to future failures. Beck's cognitive theory postulates that dysfunctional attitudes develop in response to specific stressors in the midst of an episode of depression.32
The poorer treatment outcomes of some depressive subtypes is partly explained by the patients' level of negative or dysfunctional cognitions.33
Depressed patients' interpretation of negative events also may increase the likelihood of maintaining depression and of poor response to medication.34,35
In the midst of an episode of MDD, ineffective treatment trials may constitute a specific stressor that, interpreted in a negative context, could combine with dysfunctional attitudes to result in increasingly resistant depression in some patients.
Classical conditioning also may play a role in antidepressant resistance during successive trials. Animal models have shown that pharmacologic responses to a number of different therapeutic agents can be classically conditioned,36,37
including responses to antidepressant agents.38
Similarly, pharmacologic nonresponse can also be conditioned to a reuptake inhibitor drug.39
A related concept in the classical conditioning paradigm is the process of latent inhibition, in which frequent administration of a cue (in this case, antidepressant pill-taking) that is not associated with a significant outcome prevents future conditioning to that cue,40
There is evidence to suggest that patients' physiologic responses to antidepressant medications are in part conditioned responses. A number of brain imaging studies have shown that effective antidepressant treatment is associated with decreases in metabolism or brain electrical activity in the prefrontal cortex.41,42
While these changes in function appear to be associated with antidepressant treatment, brain imaging during a placebo lead-in showed that the changes thought to be associated with successful antidepressant treatment actually preceded administration of the medication.25
These findings suggest that a psychological process such as conditioning plays a role in eliciting brain functional changes. Whether nonresponse to pharmacotherapeutic agents can be conditioned in the clinical setting by prolonged nonresponse to antidepressants has not been established.
It is difficult to demonstrate the role of expectations, cognitions, or conditioned responses in the failure to respond to successive antidepressant medication trials in humans. It is known that administration of an antidepressant is less effective after the patient has received no benefit from either a first antidepressant21
or a placebo,43
but multiple crossover trials would be necessary to determine the mechanism for this loss of effectiveness. There is clearer evidence from human pain studies, however, that ineffective medication trials directly contribute to decreases in the effectiveness of subsequent analgesic medications. The effectiveness of an analgesic medication is degraded when administered after an ineffective dose of medication or placebo; furthermore, the more doses of the ineffective compound that are given, the less likely that the analgesic will have a therapeutic effect.44,45
Blinded administration of effective analgesics also diminishes their effectiveness.46
Expectations, conditioning, and cognitive factors all have been shown to be involved in mediating these effects.46,47
In summary, unsuccessful antidepressant trials maydiminish patient expectations, reinforce negative cognitions, and condition patients not to respond during subsequent antidepressant trials. Regardless of the psychological mechanism, the above theories and data suggest that ineffective medication trials may, in and of themselves, predispose patients to experience diminished medication effectiveness in future trials.