GENETICS OF SCHIZOPHRENIA AND AFFECTIVE DISORDER - AN OVERLAP
© Psychiatry On-Line 1997 Version 1.1 First Published February 1997
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Numerous studies have established the familial aggregation of schizophrenia and that familial factors that predispose to schizophrenia also predispose to other schizophrenia related disorders. Kraepelin proposed that schizophrenia and manic-depressive psychosis were two distinct disorders but since then with abundance of literature on this subject pouring in, the theory is being challenged quite frequently. The number of studies which support the Kraepelinian view of psychosis exceed those which do not.
The proponents of continuum theory propose a continuum from unipolar to bipolar disorder to schizoaffective psychosis and right up to schizophrenia. Another hypothesis proposed is that schizophrenia and bipolar affective disorder are two distinct entities and that unipolar and schizoaffective disorders are expressed in the relatives of patients in both the categories (Gershon et al, 1988).
Rudin (1916) reported that although the risk for schizophrenia for an individual was high (6.2%) if they had a close relative with schizophrenia, it was higher if the ill relative had a non-schizophrenic (mostly affective) psychosis (8.2%) or alcoholism (7.8%). He also found almost equal numbers of relatives with affective disorder and relatives with schizophrenia in the families of his schizophrenic probands. On the other hand, among the psychotic relatives of Odegaard's (1972) manic depressive probands, 19% were diagnosed as schizophrenic, indicating that the co-occurrence may run in both directions.
Varma & Sharma (1993) reported psychiatric morbidity to be 34.78% in first degree relatives (FDR) of schizophrenics and 9.2% % in FDRs of controls. They found that schizophrenia, schizoid-schizotypal personality disorder (SSPD), paranoid personality disorder (PPD) and cannabis use disorders were more prevalent in the FDR of schizophrenics and can be used to identify samples with an increased probability of carrying the schizophrenic genotype. Various studies have reported a wide range of abnormalities thought to be related to schizophrenia, such as schizoid personality(Cadoret 1973; Stephens et al, 1975), SSPD (Baron et al, 1985; Kendler et al, 1984; Frangos et al, 1985, Varma & Sharma, 1993, Siever et al, 1993, Varma et al 1997 in press), PPD (Stephens et al, 1975; Kendler at al, 1984; Frangos et al, 1985), reactive, borderline, pseudo-neurotic, doubtful schizophrenia, manic depressive psychosis (Rosenthal et al,1971), acute delusional psychosis (Weiner, 1985), alcoholism, particularly alcoholic hallucinosis (Stephens et al, 1975), inadequate personality disorder (Kety et al, 1971), antisocial personality and behaviour (Heston, 1966; Stephens et al, 1975; Silverton, 1988 ), mental subnormality (Heston 1966), neurosis and epilepsy (Mitsuda, 1967).
Another study (Varma et al, 1997 in press) of 1089 first degree relatives of schizophrenics and 1137 controls, was carried out by us to find out the psychiatric morbidity in them. Psychiatric morbidity was found to be present in 16.34% of the first degree relatives (FDR) of schizophrenics as compared to 6.9% in the controls (p<0.001). Morbidity risk of schizophrenia was found to be 16.97, 6.22 and 5.79 for schizophrenia, schizoid-schizotypal personality disorder and depressive disorder respectively in the FDR of schizophrenic group. Other disorders also found in lesser frequency, were bipolar disorder, paranoid personality disorder, anti-social personality disorder and neurotic disorders.
Penrose (1945) reported that although schizophrenia and affective psychosis remained true in most families, "schizophrenia and affective psychosis are not very distinct entities and groups or closely related familial cases include both diagnoses". Tsuang et al (1980) concluded that their data "support the distinction between schizophrenia and affective disorders, although the distinction between schizophrenia and mania was not clear". They also concluded that their data refuted the bipolar-unipolar affective disorder subtyping. Taylor (1992) reported, "logic suggests that if bipolar and unipolar disorders are, indeed, variations of the same process and that mania and schizophrenia are related in some way, then the clear Kraeplinian dichotomy is no longer tenable".
Siever et al, (1993) has proposed that schizotypal personality disorder is related closely to chronic schizophrenia and that this disorder may be part of a continuum of schizophrenia related disorders. He questioned the method of defining the boundaries of schizophrenia, The study proposed a multidimentional approach to the pathogenesis of the schizophrenia related disorders.
Affective disorder is a heterogeneous group of psychiatric illness involving up to 20% of the population or more (Weissman & Myers, 1978)). Family studies of affective disorder have consistently demonstrated that the FDR of bipolar I probands are 8-18 times more likely than are the FDR of control subjects to have bipolar I disorder and 2-10 times more likely to have major depressive disorder. The inheritability of bipolar I disorder is also shown by the fact that about 50% of all bipolar I disorder patients have at least one parent with a mood disorder (Nurnberger & Gershon, 1992).
We have conducted another study (Varma et al, unpublished) to find out the psychiatric morbidity in the first degree relatives of bipolar affective disorder patients. Analysis has shown that significantly, more FDR of the affective disorder patients developed psychiatric morbidity than normal. The affective disorder spectrum found in the study was: depressive disorders, schizophrenia, schizoaffective disorder, attention deficit disorder, alcoholism and neurotic disorder.
The co-occurrence of schizophrenia and affective disorder has also been observed in families of affectively ill probands. Angst et al (1980), found among FDRs of their bipolar probands, the morbid risks for schizophrenia and for schizoaffective disorder were higher than expected; 1.9% and 1.5%, respectively. Scharfetter and Nusperli (1980) compared morbid risks for schizophrenia in the FDR of schizophrenic and affectively ill probands and found them to be 8.9% and 3.3%, respectively. Cyclothymia is probably genetically related to bipolar disorder (Gershon et al, 1982, Akiskal et al, 1977). Akiskal (1983) has included dysthymia, as a part of affective spectrum disorder. Affective disorder and borderline personality disorder has been reported in the families of probands with borderline characteristics themselves (Loranger 1981, Baron et al,1985). Tsuang et al 1985, stated. "if affective disorder with psychotic symptoms is not included as a subgroup of major affective disorder, then the results support the rationale behind the nosological distinction between DSM-III schizophrenia and major affective disorders". They also stated that it may be possible that some affective disorders with psychotic symptoms could be a genetic variant of schizophrenia.
Slater and Shields (1953) found that in twin pairs in which one twin had schizophrenia the prevalences of affective disorder and schizophrenia in the other twin were similar and that they had more parents with affective disorder than with schizophrenia. Later on, several studies (Farmer et al, 1987; Dalby et al, 1986) of twins with schizophrenic and affectively ill individuals also suggests some relationship between the two psychoses, as do reports of pedigrees in which the two illnesses co-occur.
Thus, from these studies it appears that the risk for schizophrenia among the relatives of affective disorder is between 0.5% - 4.0%, whereas the risk for affective disorder in the relatives of schizophrenic probands is about 6% to 8%. The literature as well as our three studies gives evidence that affective disorder and schizophrenia can occur in the families of either of the illnesses.
Schizoaffective disorder tends to fall, obviously, between schizophrenia and affective disorder. Right from the conception of the term 'schizoaffective disorder', it has been at the centre of controversy. It is now recognised as a separate entity. Schizoaffective disorder forms a very good bridge between schizophrenia and affective disorder.Logically, if it is a bridge for the main disorders then perhaps it also forms a bridge in the families of both the disorders. If the Kraeplinian dichotomy is valid then intermediate forms of psychosis, such as, schizoaffective psychosis should be rare. However, Brockington and Leff (1979) found that 8% of psychotic patients met the criteria of schizoaffective disorder. Surtees and Sashidharan (1986) found that 5.7% of the adult subjects who received psychiatric diagnosis had schizoaffective disorders. There has also been a suggestion that schizoaffective disorder is simply a more severe form of affective disorder; a third type of psychosis or a variation of schizophrenia (Taylor, 1992). This unclear separation of schizoaffective disorders and their considerable prevalence makes the case for Kraeplinian dichotomy questionable. Moreover, Kendell et al (1970a,b) failed to discriminate affective disorder from schizophrenia on the basis of various features thought to be characteristic of each disorder.
How do the results of these family studies take us beyond the existing uncertainty ? It cannot be denied that schizophrenia and affective disorders appear to be two different disorders, and that there is overlap. Longitudinal studies on the stability of diagnosis of these two disorders have not helped, because of changes in diagnostic fashion or actual chanegs in presentation itself, tending to lead to differing management plans and confusion
This review suggests that the Kraeplinian dichotomy seems to be based on shaky ground, although there are still several studies which support the dichotomy. There are insufficient data to confirm or refute the dichotomy or unitary psychosis theory at present. It may also be possible that in future we may clarify abnormalities in brain structure and function which may be pathognomonic of one of the disorders, although again the studies so far are inconclusive. Almost all family studies remain inconclusive in addressing this issue and efforts should now be directed towards finding out the significance of gene location or the pathophysiological changes of specific psychopathological phenomenon, which could discriminate further.
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