The current focus on identifying genes which predispose to psychiatric illness sharpens the need to identify environmental factors which interact with genetic predisposition and thus contribute to the multifactorial causation of these disorders. One such factor may be early parental loss (EPL). The putative relationship between early environmental stressors such as parental loss and psychopathology in adult life has intrigued psychiatrists for most of this century. We report a case control study in which rates of EPL, due to parental death or permanent separation before the age of 17 years were evaluated in patients with major depression (MD), bipolar disorder (BPD) and schizophrenia (SCZ), compared to individually matched, healthy control subjects (MD-Control, 79 pairs; BPD-Control, 79 pairs; SCZ-Control, 76 pairs). Loss of parent during childhood significantly increased the likelihood of developing MD during adult life (OR = 3.8, P = 0.001). The effect of loss due to permanent separation (P = 0.008) was more striking than loss due to death, as was loss before the age of 9 years (OR = 11.0, P = 0.003) compared to later childhood and adolescence. The overall rate of EPL was also increased in BPD (OR = 2.6, P = 0.048) but there were no significant findings in any of the subcategories of loss. A significantly increased rate of EPL was observed in schizophrenia patients (OR = 3.8, P = 0.01), particularly before the age of 9 years (OR = 4.3, P = 0.01). Comparison of psychosocial, medical and clinical characteristics of subjects with and without a history of EPL, within the larger patient groups from which the matched samples were drawn (MD, n = 136; BPD, n = 107; SCZ, n = 160), yielded few significant findings. Among the controls (n = 170), however, subjects who had experienced EPL, reported lower incomes, had been divorced more frequently, were more likely to be living alone, were more likely to smoke or have smoked cigarettes and reported more physical illness (P = 0.03-0.001). Long term neurobiological consequences of early environmental stressors such as maternal deprivation have been extensively studied in many animal species. Recently, enduring changes in hypothalamic-pituitary-adrenal axis function, including corticotrophin releasing factor gene expression, have received particular attention. Analogous processes may be implicated in the effect of EPL on human vulnerability to psychopathology, via alterations in responsiveness to stress. Genetic predisposition may influence the degree of susceptibility of the individual to the effects of early environmental stress and may also determine the psychopathological entity to which the individual is rendered vulnerable as a consequence of the stress.

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These data support the efficacy of the addition of 50 mg/day of D-cycloserine to treatment with conventional neuroleptics and suggest that therapeutic benefits may also be attained when D-cycloserine is added to olanzapine or risperidone.

Plasma prolactin levels following oral administration of the serotonin (5-HT) releasing agent, fenfluramine hydrochloride, have been extensively used to evaluate central serotonergic function in affective and related disorders. Cortisol responses to fenfluramine have generally been a less informative measure. In healthy subjects, prolactin release by fenfluramine is dose-dependent, blocked by antagonists of serotonin receptors of the 5-HT-2a/2c type, negatively correlated with age and increased in young females. In major depression, a preponderance of studies have found blunted prolactin responses compared to matched normal controls. Although a significant minority of studies have not found blunting, increased prolactin release has not been observed. The blunted prolactin release is not due to a deficient secretory capacity of pituitary lactotrophs and is congruent with other evidence for reduced central serotonergic function in major depression. Blunting of the prolactin response may be associated with severity of depression and with elevated baseline cortisol levels. Treatment with antidepressant drugs and electroconvulsive therapy has been reported to increase the prolactin response but this has not been replicated in all studies. Blunted prolactin responses to fenfluramine have been fairly consistently associated with impulsive aggression in different personality disorders and with severity of suicide attempts in depressed patients. A number of studies employing the fenfluramine challenge test (FCT) have been conducted in obsessive compulsive disorder but their results have been variable. Prolactin responses to fenfluramine may be enhanced in panic disorder and chronic fatigue syndrome but the number of studies in these conditions is small as is the case for seasonal affective disorder. Since the therapeutic administration of fenfluramine as an appetite suppressant has been suspended because of reports of cardiac complications, further use of this compound as a challenge agent is not anticipated. Future studies are likely to employ agents acting on specific serotonin receptors and should apply methodological insights from the use of the FCT, which are considered in this review. Use of concomitant brain imaging to evaluate the central effects of challenge agents directly is likely to become more prevalent and may supplant neuroendocrine challenge paradigms such as the FCT which have been remarkably heuristic but are limited in scope and methodologically complex.

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