The phenomenon of post-treatment depression in schizophrenia has become the subject of considerable controversy regarding its causality (Ananth and Chadirian, 1980; McGlashan and Carpenter, 1976a). But as the recent commentary by Hirsch (1982) emphasizes, the most controversial issue is focused on whether this depression is neuroleptic-induced. Hirsch himself refutes neuroleptic-induction on the basis of various uncontrolled data which seem ostensibly incompatible with this causality. Results indicating that pretreatment depressions appear in a high proportion of recently hospitalized schizophrenics, occur in drug-free patients, and frequently remit or decrease following neuroleptic therapy are cited as evidence contradicting neuroleptic-induction. Hirsch therefore proposes an alternative view: that this post-treatment depression is an integral, “revealed” aspect of the schizophrenia syndrome which arises from the same pathophysiological process (cf. McGlashan and Carpenter, 1976b).

SynopsisA psychopharmacogenetic strategy was used to investigate a genetic heterogeneity model of schizophrenia. This model consisted of various genetic subtypes represented by patients classified hypothetically according to the types and genealogical (Mendelian) patterns of illnesses in first-degree relatives. The effect of neuroleptics on these subtypes (drug x genetic subtype interactions) were tested for evidence of post-treatment responses which discriminated between them. The findings revealed that schizophrenics who had depressed relatives tended to exhibit (1) depression and more severe pseudoparkinsonism irrespective of types of neuroleptics, and (2) greater remission of paranoid-hostility symptoms when treated with neuroleptics of the aliphatic-piperadine type. Schizophrenics who had schizophrenic relatives failed to show these responses.Interpretation of these findings emphasized the recognition of these responses as arising from neuroleptic-induced alterations of defective neurologic-neurochemical systems underlying this subtype and as ‘pharmacogenetic criteria’ by which it can be discriminated.

The emergence of depression, parkinsonism, and akathisia after neuroleptic therapy was associated with increased length of hospital-stay in schizophrenics with affective heredity only. In schizophrenics with schizophrenic heredity, increased length of hospital-stay was associated with residual hallucinations and apathy. In the former patients, findings were theoretically attributed to a putative biogenetic abnormality sensitive to the effects of neuroleptic drugs.

Alcoholism in the male relatives of patients with various (nonalcoholic) psychiatric disorders is consistently elevated above population risk. Over the years, this finding has given rise to theories which propose that some forms of alcoholism are attributable to the pleiotropic expression of genes underlying these disorders. This mechanism was tested in the fathers of patients from ethnic groups associated with culturally suppressed alcohol abuse where it was predicted that decreased alcoholism would be substituted for by increased psychiatric disorder. Results, however, failed to support such a mechanism. Other explanations of this elevated alcoholism were considered.