Medical/Organic Factors
A large number of medical/organic factors are possible as causes of depression in patients with schizophrenia (Bartels and Drake 1988). Obviously, any medical/organic factor that can lead to a depressive syndrome in an individual who does not have schizophrenia can also lead to a depressive state in a person with schizophrenia. Such possibilities include a number of common medical conditions (anemia, cancer, neurological disorders, infectious diseases, and metabolic or endocrine disorders), various medications used in the treatment of medical problems (antihypertensive medications such as beta-blockers, sedative-hypnotics, sulfonamides, and indomethacin), and discontinuation of other prescribed medications (most typically corticosteroids and psychostimulants).

Substances of abuse, such as alcohol, cannabis, cocaine, and narcotics, can contribute to phenocopies of depression on the basis of acute use, chronic use, or discontinuation. Importantly, the discontinuation of two “legal” substances very commonly used by schizophrenia patients-nicotine and caffeine-can lead to withdrawal states that can mimic depression (Lavin et al. 1996). In particular, “smoke-free” and “decaf” policies on many inpatient units can lead to diagnostic confusion unless the possibility of withdrawal symptoms is considered in the differential diagnosis of “depressive” states.

Negative Symptoms of Schizophrenia
Conceptually, the presentation of negative symptoms in patients with schizophrenia overlaps with the syndrome of depression in a number of domains (Andreasen and Olsen 1982; Bermanzohn and Siris 1992; Carpenter et al. 1985; Crow 1980; Siris et al. 1988a). Overlapping symptoms include poor energy, diminished interest, lack of pleasure, lowered drive state, reduced motor activity, impaired concentration, and general sense of helplessness. Other symptoms, however, may be helpful in making the distinction (Barnes et al. 1989; Kuck et al. 1992; Lindenmayer et al. 1991; Norman and Malla 1991).

Blunting of affect, of course, is a feature that is more suggestive of negative symptoms, whereas prominent blue mood, sense of guilt, and suicidal thoughts are more suggestive of depression. Unfortunately, the picture is not always clear, especially since patients with schizophrenia often lack the interpersonal skills and communication abilities necessary to make their own subjective states well known.

Neuroleptic-Induced Dysphoria
Whether neuroleptic medications are “depressogenic” is an unresolved, though hotly debated, issue. Such an effect might be expected, on a theoretical basis, because dopamine synapses are involved in the brain pathways that medicate “reward” (Harrow et al. 1994; Wise 1982). Blocking of pleasure or reward by dopamine blockade, therefore, possibly could lead to anhedonia and a generalized state of depression. Indeed, one well-designed study found more anhedonia and depression in schizophrenia patients who were taking neuroleptics in the maintenance phase of treatment than in those who were not (Harrow et al. 1994).

This study built on a series of earlier, more anecdotal reports that implicated neuroleptics in the etiology of depression among schizophrenia patients (DeAlarcon and Carney 1969; Floru et al. 1975; Galdi 1983; Galdi et al. 1981; Johnson 1981a). The bulk of the controlled-study evidence, however, has tended to refute the proposition that appropriate doses of neuroleptic medication lead to the development of depressive states in individuals with schizophrenia (Knights and Hirsch 1981; Moller and von Zerssen 1986; Siris 1991, 2000). Three types of studies have been involved in this negative evidence. The first involved assessment of schizophrenia patients during the course of their treatment for acute episodes of psychosis.

When the appropriate questions were asked, it was ascertained that the greatest levels of depressive symptoms corresponded to the times when the patients were most psychotic and that the symptoms tended to resolve, albeit sometimes at a slower rate, when the psychotic episode was treated with neuroleptic medication (Green et al. 1990; Hirsch et al. 1989; Knights and Hirsch 1981; Leff et al. 1988; Moller and von Zerssen 1982; Strian et al. 1982; Szymanski et al. 1983).

These observations therefore suggest that depressive symptoms that were present before the neuroleptic was administered actually decreased during the course of neuroleptic treatment. The second group of studies comprised those that compared the ongoing course of schizophrenia in patients who were treated with neuroleptic medications with the course in those who did not receive such treatment. The patients treated with neuroleptics were not found to demonstrate more depression (Hirsch et al. 1973, 1989; Hogarty and Munetz 1984; Wistedt and Palmstierna 1983).

The third group of studies involved comparisons of schizophrenia patients with and without depression, which failed to show any differences in neuroleptic doses or neuroleptic blood levels between the groups (Bandelow et al. 1991; Barnes et al. 1989; Berrios and Bulbena 1987; Roy 1984; Roy et al. 1983; Siris et al. 1988b). Finally, relevant to this issue, one popular hypothesis concerning the pathophysiology of schizophrenia is that schizophrenia represents a disorder of dopamine regulation (Davis et al. 1991).

Simply put, this conceptualization posits schizophrenia patients as being “brittle” in terms of their dopamine regulation-that is, being vulnerable to the occurrence of dopamine storms (psychosis) and dopamine droughts (negative symptoms). Within this framework it is easy to imagine how the administration of more than the minimum required amount of neuroleptic (dopamine-blocking) medication during relatively psychosis-free intervals could exacerbate negative symptoms, which, in turn, because they can present a close phenocopy of depression as noted earlier, can give the impression of neuroleptic-induced depression.