Elsevier

Biological Psychiatry

Volume 53, Issue 8, 15 April 2003, Pages 680-690
Biological Psychiatry

Difficult-to-treat depression
Challenges in the treatment of depression with psychotic features

https://doi.org/10.1016/S0006-3223(02)01747-XGet rights and content

Abstract

Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is a most difficult form of depression to treat. Patients with MDpsy exhibit more frequent relapses and recurrences and have increased use of services, greater disability, and a poorer clinical course when compared with nonpsychotically depressed patients. Patients with MDpsy demonstrate distinct biological abnormalities in studies of the hypothalamic–pituitary–adrenal (HPA) axis, dopaminergic activity, enzyme studies, brain imaging, electroencephalogram sleep profiles, and measures of serotonergic function when compared with nonpsychotic depression. The social and occupational impairment in MDpsy has been hypothesized to be secondary to subtle cognitive deficits caused by the higher cortisol levels frequently observed in MDpsy patients. Several studies support a relationship between bipolar disorder and MDpsy, particularly in young-onset MDpsy. The most efficacious treatments for MDpsy include the combination of an antidepressant and an antipsychotic, amoxapine, or electroconvulsive therapy. Atypical antipsychotic medications may have particular relevance for the treatment of MDpsy because of the potential for reduced risk of extrapyramidal side effects and tardive dyskinesia, as well as antipsychotic and possibly antidepressant qualities. Based on the observations that MDpsy patients exhibit marked dysregulation of the HPA axis and elevated cortisol levels, several antiglucocorticoid strategies have been employed to treat MDpsy patients. Many questions regarding the acute and long-term treatment of MDpsy remain for future studies to address.

Introduction

Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is encountered frequently in clinical practice. In a study of consecutively admitted patients hospitalized for major depression, Coryell et al (1984) reported that 25% of the patients met criteria for MDpsy. In the Epidemiologic Catchment Area Study (Johnson et al 1991), 14.7% of patients who met criteria for major depression had a history of psychotic features. Although the prevalence may be as high as 45% in samples of elderly patients with major depression (Meyers and Greenberg 1986), MDpsy is not limited to older people and can occur in younger people as well. Unfortunately, MDpsy is often not diagnosed accurately because the psychosis may be subtle, intermittent, or concealed, leading to a misdiagnosis of nonpsychotic depression.

There has been a long-standing debate as to whether MDpsy is a distinct syndrome or merely represents a more severe depressive subtype (reviewed in Schatzberg and Rothschild 1996); however, in several studies, severity alone did not account for differences between MDpsy and nonpsychotic depression on measures of symptoms (Coryell et al 1984), hypothalamic–pituitary–adrenal (HPA) axis activity (Brown et al 1988), sleep (Thase et al 1986a), and treatment response Chan et al 1987, Glassman et al 1977. Other studies that have controlled for the presence of endogenous features have also observed that the differences between MDpsy and nonpsychotic depression are not simply due to differences in endogenicity. This includes studies of differentiating symptoms (Parker et al 1991), HPA axis activity Brown et al 1988, Evans et al 1983, Rihmer et al 1984, and treatment response Avery and Lubrano 1979, Chan et al 1987.

The systematic study of MDpsy has been limited by several factors: 1) the fact that the disorder does not exist as a distinct diagnostic subtype in the DSM-IV American Psychiatric Association Committee on Nomenclature and Statistics 1994, Schatzberg and Rothschild 1992; 2) very few psychiatric researchers have made the study of MDpsy a priority; 3) difficulties in enrolling patients with this disorder in research studies; and 4) the fact that the diagnosis is often missed by clinicians.

The degree of morbidity and mortality seen among patients with psychotic depression underscores the importance of intelligent and empirically guided treatment decisions, but the nature of the illness itself makes controlled treatment studies extremely difficult to execute. As a result, there have been very few controlled studies regarding the acute treatment of psychotic depression and no long-term maintenance treatment studies.

The purpose of this article is to review our current understanding of the treatment of major depression with psychotic features. First, the difficulties in accurately diagnosing MDpsy will be discussed. Next, there will be a brief review of the studies of family history, course, and biology of MDpsy. This is followed by a discussion of the possible relationship between MDpsy and bipolar disorder. The remainder of the paper is devoted to the treatment of MDpsy and is divided into sections by treatment modality: tricyclic antidepressants (TCAs), electroconvulsive therapy (ECT), combined antidepressant/antipsychotic treatment, studies with selective serotonin reuptake inhibitors (SSRIs), lithium augmentation, the role of atypical antipsychotics, hypercortisolemia and antiglucocorticoid strategies, and treatment guidelines.

Section snippets

Diagnosis

According to DSM-IV criteria (American Psychiatric Association Committee on Nomenclature and Statistics 1994), one cannot make the diagnosis of MDpsy unless one can detect the presence of delusions or hallucinations in the context of a major depressive episode; however, because the detection of delusions and hallucinations is often difficult in patients with MDpsy (Rothschild and Schatzberg 1993), a number of research groups have explored whether there are other characteristics that may help

Family history

In some studies, the first-degree relatives of patients with MDpsy exhibit higher rates of depression Leckman et al 1984, Nelson et al 1984 and the psychotic subtype (Leckman et al 1984) than do the family members of patients with nonpsychotic depression, although not all studies are in agreement Bond et al 1986, Coryell et al 1982, Coryell et al 1984, Frangos et al 1983; Maj et al 1991, Price et al 1984. In one study (Bond et al 1986), when the MDpsy group was divided by degree of HPA axis

Course

Patients with MDpsy exhibit more frequent relapses or recurrences than patients with nonpsychotic depression Aronson et al 1987, Aronson et al 1988a, Aronson et al 1988b, Baldwin and Jolley 1986, Coryell et al 1996, Helms and Smith 1983, Lykouras et al 1986, Murphy 1983, Nelson and Bowers 1978, Robinson and Spiker 1985, Rothschild et al 1993b; Spiker et al 1985); although not all studies are in agreement Coryell et al 1987, Lykouras et al 1994. Patients with MDpsy (when compared with

Biology

There exists considerable evidence from studies of the HPA axis, studies of dopaminergic activity, enzyme studies, brain imaging, electroencephalographic sleep profiles, and measures of serotonergic function that points to distinct biological abnormalities in MDpsy as compared with nonpsychotic depression. Details of these biological studies are summarized elsewhere (Schatzberg and Rothschild 1992). For example, several groups have reported specific abnormalities in HPA axis activity of

Relationship to bipolar disorder

Several studies support a relationship between MDpsy and bipolar disorder. Strober and Carlson (1982) observed 60 adolescents hospitalized with unipolar major depression. They reported a 20% conversion rate to bipolar disorder, predicted in part by a depressive symptom cluster consisting of mood-congruent psychotic features (75% of converters vs. 6% of nonconverters, p < .001), psychomotor retardation, and rapid symptom onset. Similarly, Akiskal et al (1983) observed a 20% conversion rate to

Tricyclic antidepressants

When the TCAs were introduced for the treatment of depression, reports began to appear that they were not as effective for MDpsy as in depression in general Angst 1961, Friedman et al 1961, Hordern et al 1963. One example of this is the landmark DeCarolis study (Avery and Lubrano 1979), which observed a 40% response rate in MDpsy patients treated with 200–350 mg/day of imipramine for at least 25 days. Those patients who did not respond to the imipramine then received ECT; for these patients the

Conclusions

In summary, MDpsy is associated with significant morbidity and mortality. Currently, the most effective treatments include the combination of an antidepressant with an antipsychotic, or ECT. Recent studies suggest that atypical antipsychotic medications may be effective (when combined with an antidepressant) for the acute treatment of MDpsy; however, there remain many questions for future research. Those that seem of greatest importance include the following: 1) the efficacy and safety of

Acknowledgements

Supported in part by the Irving S. and Betty Brudnick Endowed Chair in Psychiatry, University of Massachusetts Medical School.

Aspects of this work were presented at the conference, “Difficult-to- Treat Depression” held April 21–22, 2002 in San Francisco, California. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted grant provided by Eli Lilly and Company.

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