Treatment-Resistant Unipolar Depression: Depressive Subtypes and Treatment Response
Since the introduction of TCAs in the 1950s, clinicians and clinical researchers have attempted to define depressive subtypes to predict response to these drugs. The clinical relevance of the different proposed subtypes that have emerged over the years has been tested in a number of clinical trials, although some results have been conflicting. Several studies, however, have presented convincing evidence of an association between poor outcome and/or resistance to treatment and specific depressive subtypes. The following subtypes should be considered when assessing the causes of nonresponse to antidepressants.

Melancholic Depression
Melancholic features are characterized, according to DSM-IV (American Psychiatric Association 1994) by either nonreactivity of mood or pervasive anhedonia plus three or more of the following: distinct quality of mood, depression worse in the morning, early morning awakening, marked psychomotor retardation/agitation, significant anorexia/weight loss, and excessive or inappropriate guilt. The validity of this subtype has been supported by the work of Paykel and has more recently been evaluated by Coryell et al., Rush and Weissenburger, and Amsterdam. In particular, Coryell et al. found a significant stability of this pattern for subsequent episodes. This subtype of depression is more common among inpatients than outpatients, is less likely to be associated with external precipitants (endogenous), and has a high familial loading. Whereas TCAs typically are effective treatments for endogenous/melancholic depression, non-TCAs have been thought to be relatively less effective. When adequate doses are prescribed, however, agents such as MAOIs and SSRIs are generally at least as effective. In fact, paroxetine, fluvoxamine, sertraline, and fluoxetine were found to be as efficacious as TCAs in severe/melancholic depression. These results challenged the idea that this depressive subtype is a potential contributing factor for resistance to treatment with SSRIs.

The possibility that dual-action antidepressants may be more efficacious than SSRIs in the treatment of severe melancholic depression has been supported by studies with clomipramine, venlafaxine, and mirtazapine. On the other hand, other studies have failed to show that either clomipramine or venlafaxine was in fact superior to the SSRIs sertraline and fluoxetine, respectively. Further studies are necessary to clarify whether dual-action antidepressants are indeed more efficacious than other antidepressants in this depressive subtype. The possibility remains that melancholic patients, who are also typically more severely ill, may require greater intensity of pharmacotherapy in general.

Atypical Depression
The term atypical depression describes a number of nonendogenous, mood-reactive subtypes of depression. A review of the literature supports the notion that the diagnostic category of atypical depression has clinical utility, as well as preliminary evidence of distinctive physiological and biochemical features. In the most widely studied variation and according to the DSM-IV classification, atypical depression is defined by mood reactivity and two or more of the associated features of overeating, oversleeping, extreme fatigue when depressed, or chronic oversensitivity to rejection. Of 119 patients with atypical depression, 71% responded to phenelzine, 50% to imipramine, and 28% to placebo. In a crossover study of patients with depression who had not responded to the combination of imipramine and interpersonal psychotherapy (IPT), Thase et al. (1991) found that a significantly greater proportion of patients with atypical depression (78%) responded to MAOI treatment compared with the patients with nonatypical depression (38%). A study by Jarrett et al. (1999) showed that cognitive therapy is as effective as the MAOI phenelzine in treating atypical depression and both treatments were superior to placebo, suggesting that cognitive therapy may be an effective alternative to standard treatment with an MAOI.

The well-established superiority of MAOIs compared with TCAs has not been typically translated into the selection of MAOIs as first-line agents for this subtype. As pointed out by Nierenberg et al., because of the favorable benefit-risk ratio, clinicians tend to use the newer antidepressants, in particular the SSRIs, in patients with atypical depression, even though the literature on their use is quite limited. However, a study by McGrath et al. showed fluoxetine to be superior to placebo but only as effective as the TCA imipramine, whereas a study by Pande et al. showed no significant difference in efficacy between fluoxetine and the MAOI phenelzine. A small open trial suggests the efficacy of bupropion in the treatment of atypical depression, but further studies are needed to confirm this impression. These studies suggest that patients with atypical features are relatively resistant to treatment with TCAs but not to MAOIs and possibly SSRIs and bupropion.

Double Depression
Keller and Shapiro first introduced the concept of “double depression,” a major depressive episode in the course of a chronic minor depression of at least 2 years’ duration. Keller and Russell suggested that patients with a history of double depression should be considered separate from patients with pure dysthymia. Keller et al. found that patients with double depression recovered quickly from the major depressive episode but took much longer to recover from the chronic minor depression. These data suggest that the presence of major depression superimposed on chronic, nonmajor depression reduces the chances of full remission but not those of partial response. Furthermore, in the Medical Outcomes Study, patients with double depression or dysthymia alone had worse outcomes than those with major depression alone. Pava et al. postulated that the addition of specific forms of psychotherapy, in particular cognitive therapy, may facilitate remission in patients with double depression and only partial responses to antidepressants alone.

Psychotic Depression
Psychotic features of major depression typically include delusions or hallucinations. This subtype of unipolar depression is more likely to affect older patients. Delusions can be broadly classified as guilty, paranoid, or somatic; hallucinations may be auditory, visual, or somatic. Coryell et al. reported in a study that the psychotic subtype of depression had the most enduring diagnostic stability across multiple subsequent episodes.

Glassman et al. found only 3 of 13 patients with delusional depression to be responsive to a 4-week-long treatment of imipramine, but 14 of 21 patients who were nondelusional responded. Similar findings were reported by Chan et al.. In addition, this depression subtype was found to be associated with relatively poorer outcome at 1-year follow-up.

The relative refractoriness of psychotic depression to antidepressant treatment alone suggests that psychotic symptoms require additional specific treatments. In a prospective study, Spiker et al. demonstrated superior efficacy for treatment of psychotic depression using a combination of an antidepressant and an antipsychotic drug compared with monotherapy with an antidepressant.

Unipolar delusional depression can be further subclassified as mood congruent or mood incongruent and as being of early onset or late onset. Although the subclassification of mood congruence or incongruence does not influence the rate of response to acute pharmacotherapy, patients whose delusional depression is of late onset are more likely to be treatment-resistant. Overall, patients with psychotic features are relatively resistant to treatment with antidepressants alone, with the possible exception of amoxapine, which is variably and in part metabolized to an antipsychotic.

Thus, the combination of an antidepressant and a traditional antipsychotic drug is required for most patients with psychotic depression. The reports of efficacy of SSRIs alone in the treatment of psychotic depression by an Italian group of researchers have not been replicated. Furthermore, given the extremely high rates of this subtype reported by this group, issues concerning the accuracy of the diagnoses made in those studies have been raised. In particular, the double-blind comparison of sertraline and paroxetine (Zanardi et al. 1996) found a rate of response to sertraline alone higher (75%) than those observed in studies with a TCA alone (40%) and comparable to the rates observed with a TCA plus an antipsychotic and an SSRI plus an antipsychotic. Rothschild and Phillips wondered in the commentary whether some of the patients enrolled into these two Italian studies might have met criteria for body dysmorphic, obsessive-compulsive, or borderline personality disorders that may be characterized by depression plus delusional or near-delusional beliefs or other psychotic or psychotic-like symptoms that preliminary evidence suggests may respond to SSRIs alone. On the other hand, the need for the concomitant use of antidepressants in patients treated with atypical antipsychotic agents has been questioned, given the preliminary observations that monotherapy with the atypical antipsychotic agents clozapine, risperidone, and olanzapine may be efficacious in patients with psychotic depression, even when they are refractory to treatment.

Depression With Concurrent Psychiatric or General Medical Illnesses

Comorbidity can be defined as the presence of any condition other than the illness under treatment or investigation. In one study, patients with depression and concurrent Axis I, Axis II, or Axis III disorders were found to report significantly poorer functioning during the 12-month follow-up period and to have lower recovery rates than patients with depression alone. Although these results suggest that comorbidity in general may contribute to resistance to antidepressant treatment, only certain specific concurrent conditions may specifically affect response, while the presence of certain other comorbid conditions may have little impact on treatment outcome.

The outcome for patients with depression and a concurrent disorder will be influenced by the efficacy of the selected treatment for both the depression and the concurrent condition. For example, comorbid depression and obsessive-compulsive disorder (OCD) will be less responsive to a TCA, other than clomipramine, than to an SSRI. Indeed, some of the recent successes of the SSRIs as a class derive from the fact that these drugs appear to be effective not only in depression but also in a number of psychiatric illnesses, such as OCD, panic disorder, bulimia nervosa, posttraumatic stress disorder (PTSD), and borderline personality disorder. Because the effectiveness of antidepressants in the treatment of nonmood psychiatric disorders varies across antidepressant classes, resistance in a depressed patient with comorbid conditions may reflect failure of the selected antidepressant to treat the concurrent disorder. When no class of antidepressant is known to be effective in the treatment of the comorbid condition, other psychotropic drugs (i.e., antianxiety and antipsychotic drugs) with efficacy in the treatment of the concurrent disorder are indicated.

Unrecognized concurrent medical conditions can also contribute to treatment resistance. In one study, unrecognized medical illness either caused or exacerbated psychiatric symptoms in up to 46% of psychiatric inpatients. Furthermore, concurrent medical conditions may contribute to treatment resistance even when recognized and treated. In a study on outcome of psychiatric treatment in medically ill patients, only 40% of patients with concurrent medical conditions responded to antidepressant treatment. Folate deficiency has also been shown to be associated with a poorer response to fluoxetine treatment among depressed outpatients.

For these reasons, clinicians should always consider the possibility of medical comorbidity contributing to resistance in depressed patients and gather medical history in a systematic fashion before embarking on further treatment steps. Routine laboratory, vitamin B₁₂, folate, and thyroid function tests together with careful medical history taking represent adequate medical evaluations of patients who have not responded to an antidepressant trial of adequate dose and duration.

Finally, it is essential to consider that Axis IV problems negatively affect the outcome of antidepressant treatment. For example, the presence of severe family conflicts and the relative absence of family support may predict poor outcome for depressed patients, and multiple losses through death of family members are significantly correlated with chronicity in primary depression. Overall, psychiatric and medical comorbidity in depression is a potential source of resistance, frequently indicating that one should consider a specific antidepressant selection or the combination of treatments or agents from different classes.

Anxious Depression
Anxiety and nervousness are common among patients with major depression. Fawcett and Kravitz found that depressed patients reported high rates of excessive worrying (72%), psychic anxiety (62%), and somatic anxiety (42%). A dimensional approach to the overlap between anxiety and depressive disorders is to classify major depressions with high levels of anxiety as anxious depression. Anxious depression has been found to be associated with greater severity of both illness and functional impairment, chronicity, and delayed response or poorer rates of response to antidepressants.

Some regard TCAs to be superior to the SSRIs in treating anxious depression. However, in three large meta-analyses the SSRIs fluoxetine and paroxetine were found to be as efficacious as TCAs in reducing anxiety and agitation in depression. Moon et al. (1994) also found sertraline to be as effective as clomipramine, a TCA, in anxious depression. In addition, a study of 336 health maintenance organization primary care patients randomly assigned to an initial prescription for the SSRI fluoxetine or imipramine showed that baseline levels of anxiety did not predict significant differences in improvement between the two treatment groups. Finally, a recent study showed no significant differences in efficacy and tolerability of fluoxetine, sertraline, and paroxetine in patients with high levels of baseline anxiety symptoms during the acute treatment of major depression.

Depression With Panic Attacks
Depressed patients who have panic attacks have been reported to have significantly poorer outcomes than those who do not have panic attacks. On the other hand, in one report on patients with atypical depression, the superiority of either phenelzine or imipramine to placebo was largely confined to patients with a history of spontaneous panic attacks, although this positive predictive role of panic was not replicated in later studies. Whether patients with nonatypical depression and co-occurring panic attacks are less likely to respond to antidepressant treatment than those without panic attacks deserves further study.

Depression With Anger Attacks
Anger attacks are present in about one-third of depressed outpatients and are accompanied by a distinct psychological and neuroendocrine profile—specifically, a blunted prolactin response to fenfluramine challenge compared with those who do not have anger attacks. A recent review by M. Fava and Rosenbaum (1999) showed that this subtype of depression is associated with specific patterns of concurrent Axis II psychopathology as well. Anecdotal evidence suggests that relatively noradrenergic TCAs may be less effective than SSRIs in the treatment of this “hostile” depressive subtype with prominent irritability and anger and with a neuroendocrine response to fenfluramine challenge consistent with a relatively greater dysregulation in serotonergic neurotransmission. In two large open studies, patients with depression and anger attacks showed a very good response to treatment with the SSRI fluoxetine. Further studies are needed to compare the efficacy of selective noradrenergic and selective serotonergic agents for depression with high levels of anger/irritability.

Depression With Concurrent Personality Disorders
Personality disorders are frequently present in depressed patients. Shea et al. (1992) reviewed the results of several studies (mostly naturalistic) to conclude that depressed patients with concurrent personality disorders show a significantly poorer response to antidepressant medication (primarily TCAs) than do those without a personality disorder. The presence of concurrent personality disorders was not, however, associated with poorer outcomes in a large sample of depressive outpatients treated with the SSRI fluoxetine. Instead, patients meeting criteria for Cluster B personality disorders (i.e., histrionic, narcissistic, borderline, and antisocial) did significantly better than those without Cluster B disorders. Furthermore, patients with atypical depression meeting criteria for borderline personality disorder improved less with TCA therapy than with the MAOI phenelzine. In summary, for depressed patients with concurrent personality disorders, resistance to treatment may vary considerably depending on the medication selected.

Depression With Concurrent Substance Abuse
Although many patients with unipolar depression have a lifetime history of alcohol and/or substance abuse, some clinicians consider the presence of comorbid substance abuse in depressed patients to be a relative contraindication to treatment with antidepressants. In clinical studies, ongoing substance abuse was found to be present in a high proportion of patients who had partial response and nonresponse to antidepressant treatment. Unsuccessful recovery in primary depression has been reported to be highly associated with secondary “sedativism” (including alcoholism). There is some evidence that the concomitant mild or moderate use (not abuse) of psychoactive substances, such as alcohol, has a negative effect on outcome among outpatients with major depression. In general, most clinicians recommend abstinence from alcohol and other drugs of abuse for patients undergoing antidepressant treatment.