Early intervention for individuals experiencing their first episode of psychosis has a high likelihood of resulting in remission of psychotic symptoms. However, it is common for patients in remission following a first episode of schizophrenia to experience persistent difficulties in everyday functioning. A large percentage of such individuals have difficulty working and find themselves disabled and unable to support themselves (5,6). It is believed that this disability develops in the years preceding the onset of psychotic symptoms, the prodromal period, in which social withdrawal and the evolution of negative symptoms form the base upon which psychotic symptoms subsequently develop (7).

One of the major retrospective studies of the onset of schizophrenia, the Mannheim Age, Beginning, Course (ABC) study (8), showed that 73% of 232 patients hospitalized for first-episode schizophrenia had experienced a prodromal phase with negative and nonspecific symptoms. Twenty-seven percent reported an acute illness onset with positive symptoms (7%) or positive and negative symptoms occurring within one month (20%). No gender differences were observed in this aspect of the prodrome. On average, the prodromal phase lasted five years and was followed by a psychotic prephase of 1.1 years, which was characterized by the first occurrence and escalation of positive symptoms. Thus, independent of gender, before the first inpatient treatment for schizophrenia, the majority of individuals were ill for more than six years.

In line with the finding of the Determinants of Outcome study by the World Health Organization (WHO) (9), the ABC study found an average three to four years difference between males and females in the milestones of the early course (i.e., first sign, first negative symptom, first positive symptom, first episode, and first admission), with men reaching each of these milestones earlier than women (8). The distribution of age of onset of the illness (i.e., occurrence of the first sign) showed an early and steep increase for men, with a pronounced peak between 15 and 25 years of age and a decrease in the later years. In women, the increase was less steep, with the peak lower and later, between 15 and 30 years of age. A brief decline in incidence thereafter was followed by a second, lower peak around menopause, age 45 to 49. In adolescence and early adulthood, men are at a twofold risk of morbidity for schizophrenia in comparison to women. Consequently, studies of adolescent schizophrenia tend to report a male:female ratio of 2:1. This ratio has also been observed in first-episode studies (5,6). In a Canadian sample of 361 first-episode subjects, there was a significant gender difference in age of onset (5,6). Males were significantly younger for the onset of a schizophrenia spectrum disorder and of schizophrenia. However, no other gender differences such as DUP, symptoms, insight, social, or cognitive functioning have been observed in this first-episode group (5,6).

The gender difference in age of onset does not exist in subjects who have a family history of schizophrenia (10). Similarly, women with schizophrenia with a history of prenatal and perinatal complications show an onset age similar to that of men (11). One explanation for the gender disparity in age of onset of schizophrenia is a putative protective effect of estrogen that can be overridden by genetic and other factors (12,13). Support for the estrogen hypothesis is offered by commonly occurring premenstrual, postpartum, and postmenopausal exacerbations of schizophrenia, by the relative freedom from relapse during pregnancy, and by the approximately threefold increased risk of schizophrenia during the 90 days after childbirth (14), as well as by the significant relationship between age of menarche and age at onset of schizophrenia in women. A late age of menarche has been reported to be related to an earlier onset (15). For women lacking additional risk factors, schizophrenia is not necessarily a disorder that first shows itself in adolescence, as it almost always is in men. (Jayashri Kulkarni addresses gender issues in adult schizophrenia more fully in Chapter 14 of this book.)

Häfner found gender similarity in patterns of course, symptomatology, and neuropsychological functioning in schizophrenia (8) and concluded that it was “important to analyze gender differences in variables more distant to the disease process” (p. 204). Such an opportunity exists in early detection and intervention research in the initial prodrome of first-episode psychosis.

The term “prodrome” is retrospective because, until psychotic illness develops, no prodrome can be said to have existed (16). The prodrome refers to the time between the appearance of mental state features that represent a change from a person’s premorbid functioning until the onset of frank psychosis (16). Approximately 80% to 90% of patients with schizophrenia report a variety of symptoms (including changes in perception, beliefs, cognition, mood, affect, and behavior) that preceded psychosis; and only 10% to 20% develop psychotic symptoms without any apparent significant prodromal period (8,17). Nonspecific symptoms and negative symptoms usually emerge first, followed by attenuated positive symptoms (13). These earliest signs do not differ significantly between men and women (8). The most pronounced gender difference has been found for social behaviors. Men more often than women present a history of drug or alcohol abuse and social disability. They are also more likely to show inadequate personal hygiene, reduced interest in acquiring a job, social inattentiveness, lack of free-time activities, and deficits in communication (8). These results fit with findings from genetic high-risk and birth-cohort studies that indicate clear gender-specific differences in social behavior: girls developing schizophrenia were introverted throughout childhood into adolescence; boys were disagreeable and less socially integrated, but only in the later school grades (18). These very early aberrations do not seem to interfere with social role performance prior to the onset of the first sign of the illness but, by the time of first admission, a functional advantage for young women is already evident (8). Further examination of study data reveals a significant interaction of gender and preillness social behaviors as a determinant of the medium-term social outcome of schizophrenia (19).

High-risk groups selected by positive family history of a first-degree relative with schizophrenia have long been identified in schizophrenia research, and several prospective longitudinal studies are currently ongoing (20). In these genetic high-risk studies, the risk of converting to psychosis is still relatively low, approximately 10% to 20% (20). However, if prepsychotic intervention is the goal, then we need to reach those whose risk of converting to psychosis is much higher than 10% to 20%.

Based on clinical observations and retrospective research on the prodromal phase of first-episode psychosis, the so called ultrahigh-risk (UHR) criteria of the initial prodrome of psychosis were developed and prospectively refined at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne (4). The criteria include the recent onset of a functional decline plus genetic risk, or recent onset of subthreshold or brief threshold psychotic symptoms. Using these new criteria, the risk of converting to psychosis increases from 10% to 20% in the genetic high-risk group to approximately 40% to 60%. This has been reported in several studies (21).