Giovanni A Fava Stefania Fabbri

There is increasing awareness that the majority of depressed patients fails to respond to an appropriate trial of antidepressant drug of adequate dose and duration (less then 25% symptom reduction from baseline) or shows a partial response (25-49% symptom reduction from baseline), or achieves a response without remission (50% or greater symptom reduction from baseline but presence of residual symptomatology) (Fava, 2003). Several pharmacological strategies have been developed for depressed patients who fail to respond to standard drug treatment (Fava, 2003; Fava & Rush, 2006; Thase & Rush, 1995) but limited research has been done on nonpharmacological approaches despite the logical appeal of treating patients who do not respond to antidepressant medication with psychotherapy (McPherson et al., 2005). There has been an upsurge of research, however, on cognitive strategies in prevention of relapse of mood disorders (Fava, Ruini, & Rafanelli, 2005). In this chapter, we discuss the role of cognitive therapy (CT) in drug-resistant depression and when remission is partial and associated with substantial residual symptomatology.


There is no accepted definition of "drug-resistant depression" (Fava, 2003; Sackeim, 2001). The most common definition is failure to achieve a satisfactory response to at least one antidepressant trial of adequate dose and duration. A more conservative definition is a poor response to two appropriate trials of different classes of antidepressants (Fava, 2003).

We report here an abridged account of our cognitive protocol developed from standard cognitive strategies. Unfortunately, because large-scale, randomized controlled trials of CT in the treatment of resistant depression have not been published yet, our suggestions are purely tentative, based only on an open trial and on our experience in our Affective Disorder Program.


A first issue that is important when assessing a case of drug-resistant depression is that of "pseudoresistance." Nierenberg and Amsterdam (1990) used this expression in reference to nonresponse to inadequate treatment, in terms of duration or dose of the antidepressant used. Certain pharmaco-kinetic factors, such as concomitant use of metabolic inducers (e.g., drugs that may increase the metabolism and elimination rate of coadministered agents) may also contribute to the phenomenon of pseudoresistance. In the Affective Disorder Program, our very conservative definition of "treatment-resistant depression" (TRD) is the persistence of major depression despite at least two courses of adequate drug treatment. "Appropriate drug treatment" is defined as use of standard doses of antidepressant drugs administered continuously for a minimum duration of 6 weeks. Furthermore, as suggested by Simpson and Kessel (1991), one trial should include the use of a high-dose (200-300 mg) tricyclic, such as imipramine, for a minimum of 6 weeks.

Another aspect of pseudoresistance concerns patients who are mis-diagnosed as having unipolar depressive disorder (Nierenberg & Amsterdam, 1990) when they have suffering from diseases such as bipolar illness, vascular dementia, or anxiety disorders. But even when unipolar depression disorder is confirmed by a careful assessment, the issue of comorbidity needs to be explored (Fava et al., 2005).

The majority of depressed patients qualify not for one, but for several Axis I and Axis II disorders, which is exemplified by the occurrence of comorbidity in major depression (van Praag, 2000). Very seldom do these different diagnoses undergo hierarchical organization or is attention paid to the longitudinal development of disorders (Fava & Kellner, 1991; e.g., the primary-secondary distinction in depression; Feighner et al., 1972). There is comorbidity that wanes upon successful treatment of one disorder (e.g., recovery from major depression may result in remission from co-occurring hypochondriasis), without any specific treatment for the latter (Kellner, Fava, Lisansky, Perini, & Zielezny, 1986). Other times, treatment of one disorder does not result in the disappearance of comorbidity. For instance, successful treatment of depression may not affect preexisting anxiety disturbances (Fava, Rafanelli, Grandi, Conti, & Belluardo, 1998). As a result, longitudinal development of disorders may not always provide a hierarchical link, and the response to treatment should be evaluated.

Emmelkamp, Bouman, and Scholing (1992) distinguish two levels of functional analysis in psychological assessment: "macroanalysis" (a relationship between co-occurring syndromes is established on the basis of where treatment should commence) and "microanalysis" (a detailed analysis of symptoms). For instance, a patient may present with a major depressive disorder, obsessive-compulsive disorder, and hypochondriasis. In terms of macroanalysis, the clinician may give priority to the pharmacological treatment of depression, leaving to posttherapy assessment the determination of the relationship of depression to obsessive-compulsive disorder and hypo-chondriasis. Will they wane as depressive epiphenomena, or will they persist, despite some degree of improvement? In this latter case, should further treatment be necessary? What type of relationship do obsessive-compulsive symptoms and hypochondriasis entertain? On the basis of the type and longitudinal development of hypochondriacal fears and beliefs (Savron et al., 1996), the clinician may decide to tackle the obsessive-compulsive disorder, regarding hypochondriasis as an ensuing phenomenon, or he/she may consider them as independent syndromes. Thus, macroanalysis allows disentangling of the complexity of comorbid disorders by establishing treatment priorities. The clinician may in fact decide not to consider drug-resistant depression as the primary target of treatment but to concentrate his/her efforts on a co-occurring syndrome.

A final aspect that needs to be explored in assessing the patient is the presence of medical comorbidity: Several disorders (e.g., Cushing's syndrome, hyperprolactinemia) in their acute phase hinder satisfactory response to antidepressant drugs (Fava & Sonino, 1996).

Defeat Depression

Defeat Depression

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