[1] 16w Premorbid behavioral and intellectual functioning in schizophrenia patients with poor response to treatment with antipsychotic drugs

[1] 166w Introduction: Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment. Method: One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions. Results: As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p = 0.002], and individual autonomy [p b 0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p N 0.1]. Conclusions: Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.

[1] 68w Despite the proven efficacy of anti-psychotic medications, approximately one third of all schizophrenia patients show poor response or remain resistant to pharmacological treatment (Davis et al., 1980;Lieberman et al., 1993). Although some benefit from treatment with Clozapine, these constitute a very small proportion of the poor response patients. This finding has been consistent over time, and the management of poor response patients remains a persistent public health problem.

[2] 86w The traditional definition of poor response and of treatment resistance is pharmacologically driven and includes failure to benefit from treatment with two different classes of anti-psychotic agents (Kane et al., 1988). The more recent definition includes the persistence of moderate to severe positive and negative symptoms despite an adequate trial of two anti-psychotic drugs together with the persistence of other symptoms such as cognitive, social and occupational impairments, behavioral problems and mood and anxiety symptoms for a prolonged period of time (Brenner et al., 1990;Lindenmayer, 2000).

[3] 150w Poor response to treatment has been associated with several clinical and demographic characteristics, including male gender, early age of illness onset, family history of schizophrenia, absence of affective symptoms, longer duration of untreated psychosis, severe negative symptoms, presence of soft neurological signs, lateral and third ventricular enlargements, and low catecholamine levels in the CSF (for a detailed review of the topic see : Caspi, 2004). Several studies have also examined the relationship between premorbid functioning and treatment response. Results of these studies have been mixed, with some studies showing that poor premorbid functioning is associated with poor response to treatment (Keefe et al., 1989;Rabinowitz et al., 2006), while others found no association (Findling et al., 1996). These studies relied predominantly on retrospective reports to evaluate premorbid functioning. Such reports could be biased by selective or incomplete recall on the part of the patients or family members (Rabinowitz et al., 2006).

[4] 82w In an attempt to elaborate of the phenomenology and biology of poor response to treatment, the present study examined premorbid intellectual and behavioral functioning of schizophrenia patients who showed poor response to antipsychotic drug treatment using a historical albeit prospective population-based casecontrol design. Patients were ascertained from the Israeli National Psychiatric Hospitalization Case Registry and a treatment resistance registry, and information about premorbid functioning was obtained from the Israeli Draft Board mandatory assessment of intellectual and behavioral functioning conducted at age 17.

[1] 147w Table 1 presents the scores of treatment-resistant and treatment non-resistant patients on the cognitive and behavioral measures. Future treatment-resistant male patients had significantly lower premorbid social functioning and individual autonomy scores in comparison to future treatment non-resistant male patients (p b 0.005, p b 0.000, respectively). No significant differences in premorbid organizational ability or physical activity were evident. No significant difference in premorbid intellectual functioning between treatmentresistant and treatment non-resistant patients was observed in either males or females [48.98 ± 18.60 vs. 49.38 ± 18.89, t(93) = 0.17, p = 0.86; and 51.26 18.16 vs. 56.03 18.90, t(34) = 1.42, p = 0.16, for males and females treatment-resistant and treatment non-resistant patients, respectively]. Treatment-resistant patients had a significantly lower (earlier) age of first psychiatric hospitalization [22.1 ± 3.6 vs. 23.4 ± 5.4, for treatmentresistant and treatment non-resistant patients, respectively; t(df = 128) = 3.04; p = 0.002].

[2] 123w To further explore the association between poor premorbid social functioning and individual autonomy and subsequent risk for poor response to treatment, a multivariate logistic regression model was used. The logistic model indicated a significant association between abnormal premorbid social functioning and individual autonomy and risk for poor response (Wald χ 2 = 10.53, df = 2, p = 0.005). Abnormal premorbid individual autonomy was associated with a two-fold increase in risk for being classified as a treatment nonresponder (OR = 2.02, 95%CI: 1.29-3.16), and abnormal premorbid social functioning was associated with a 1.7 increase in risk for being classified as a treatment non-responder (95%CI: 1.10-2.53). Adding age of first admission to the regression model attenuated the association for social functioning (p N 0.1).

[1] 155w To he best of our knowledge this is the first population-based case-control prospective study of the relationship between premorbid functioning and treatment response. The main finding of this study is that future poor response male schizophrenia patients showed lower premorbid social functioning and individual autonomy at ages 16-17 compared with treatment non-resistant male patients. Draft Board assessment of social functioning includes evaluation of the quality and quantity of social relations, and the motivation to seek social interactions. Impaired individual autonomy is characterized by a lower level of autonomy in taking action and making decisions, individually or in a group. Impaired social functioning and individual autonomy can thus be viewed as complementary facets of social performance. Therefore, the results of the present study go in line with findings from previous studies that identified impaired social performance as a predictor of worse outcome and poor response to treatment in schizophrenia (Findling et al., 1996;Wieselgren and Lindstrom, 1996).

[2] 112w Strengths of the present study include the use of a population-based registry of treatment non-responders, and the availability of prospectively collected premorbid data. Limitations of this study include the use of clinical, rather than research diagnosis, as well as the fact that the clinical data on the poor response patients are limited, derived from a database, and do not include significant variables such as whether the poor response was due to enduring negative or positive symptoms. The patients included were only inpatients, thus findings may not apply to less severely ill patients. Nevertheless, at the year in which the cohort was created the initiation of Clozapine treatment was possible only during hospitalization.

[3] 70w Poor social functioning and individual autonomy might be markers of schizotypy. Schizotypy has been associated with poor outcome and response to treatment (Bailer et al., 1996). However, subjects who received any psychiatric diagnosis during the Draft Board screening, including a diagnosis of schizotypal personality disorder were excluded from analysis. Finally, since the Draft Board conducts assessment of behavioral functioning only in males, the results may not be generalizable to females.

[4] 135w In summary, in a population-based study, in males, poor response to treatment was associated with poorer premorbid social cognition. Although the specific mechanisms underlying poor response remain unknown, the present study suggests that the etiology of the condition is associated with neurodevelopmental components characterized by premorbid impairments in social functioning and individual autonomy. Early detection of poor response in schizophrenia is of major importance as it could lead to the early use of specific treatment strategies such as the use of Clozapine and early rehabilitation. A reduction of duration of positive psychotic symptoms was shown to improve outcome in schizophrenia (Marshell et al., 2005;Perkins et al., 2005). Furthermore, one could expect that an early rehabilitative effort invested in those patients who are expected to show resistant negative symptoms could reduce their social and occupational withdrawal.

[1] 29w This study builds on the linkage of three national registries: The Israeli National Psychiatric Hospitalization Case Registry, a national registry of treatmentresistant patients, and the Israeli Draft Board registry.

[2] 50w As described in detail elsewhere (Davidson et al., 1999) the intellectual test battery consists of four tests assessing verbal and non-verbal reasoning, verbal processing speed, and mathematical knowledge. The four tests form a 9-point summary score which is a valid measure of general intellectual ability (Davidson et al., 1999;Gal, 1986).

[3] 200w The behavioral assessment is performed only in males, and is conducted by a trained psychometrician who administers a semi-structured interview evaluating: (a) social functioning which assesses social potency (e.g., likes to take charge, likes to be noticed at social events), and social closeness (e.g., sociable, has close interpersonal relationship), (b) individual autonomy which assesses the ability to deal with social situation the require action, level of personal autonomy, maturity and self-directed behavior (e.g., ability to function and make decisions independently, handle group pressure and interact with groups), (c) organizational ability which assesses compliance to time tables, self-mastery and self-care (e.g., ability to adhere to a schedule and tidiness responsibility), and (d) physical activity which assesses the involvement in extra curricular activities concentrating in health-related physical activities (e.g., interest in sports and hiking). Each behavior is rated on a 5-point Likert scale with scores range between 1 (very poor) to 5 (exceptional). The test-retest reliability of the behavioral assessment for inductees interviewed after several days by different interviewers is above 0.8, and population-based norms are available (Gal, 1986;Reeb, 1968). Thus, scores of 1 or 2 represent abnormal functioning (for a more detailed description of the interview see: Rabinowitz et al., 2000).

[4] 84w The National Psychiatric Hospitalization Case Registry and MOH 1998 Clozapine registry files were merged with the Draft Board file by the managers of the registry using an algorithm to preserve medical record confidentiality (Rabinowitz, 1998) and in compliance with local IRB approval. The linking variable was the unique individual identification number (ID, equivalent to the US Social Security number). The merger identified 273 poor response patients suffering from schizophrenia, schizoaffective disorder or psychotic disorder NOS who were assessed by the Draft Board after 1985.

[5] 145w Subjects with comorbid Axis-I diagnoses and subjects suffering from a neurological disorder according to the MOH psychiatric hospitalizations registry were excluded. In addition, in order to ensure that the Draft Board data represent premorbid functioning, subjects who were hospitalized in a psychiatric ward prior to the Draft Board assessment or within 1 year following the assessment and subjects who received any psychiatric or neurological diagnosis during the Draft Board screening were also excluded. The remaining file included 129 subjects (hereafter: treatment-resistant patients), 94 of them males. 122 of cases had a registry last discharge diagnosis of schizophrenia, 4 of schizoaffective disorder, and 3 of psychotic disorder NOS. Subjects were 36.05 (± 3.58) years old, and had 11.15 (± 1.42) years of formal education. The average number of years between subjects' first psychiatric hospitalization and the year Clozapine was prescribed was 6.74 years (± 4.86 years).

[6] 64w Cases were matched for gender, year of birth, number of years of formal education and last discharge diagnosis with 129 psychiatric registry patients who were not included in the Clozapine registry and who were also assessed by the Draft Board (hereafter: treatment nonresistant patients). The same inclusion criteria and the same criteria for the establishment of diagnosis were held for the treatment responders group.

[7] 115w Paired-sample t-tests were used to compare age of first psychiatric hospitalization between treatmentresistant and treatment non-resistant patients. Pairedsample t-tests were also used to compare premorbid behavioral and intellectual functioning between the patients groups. Since the Draft Board's behavioral assessment is administered to males only, analyses were conducted separately for males and females. Significance levels were set at 0.05. Conditional logistic regression was used to examine the association between poor premorbid intellectual and behavioral functioning and risk for subsequent treatment non-response. Odds ratio (OR) and 95% confidence intervals (95%CI) were computed. p-values were calculated using Wald chisquare, and significance level was set at 0.05 (twosided). For this analysis premorbid measures were dichotomized to abnormal or normal.

[1] 105w The National Psychiatric Hospitalization Case Registry includes a complete listing of all psychiatric hospitalizations since 1950 regardless of type and auspices (public or private) of facility. A special department of the Israeli Ministry of Health (MOH) verifies compliance of reporting, completion of forms, and consistency of information. The source of the data is the report of the treating board certified psychiatrist who is required by law to complete a form that is entered into the case registry for any admission and discharge to a psychiatric bed in Israel. Registry diagnoses have shown good sensitivity and specificity when measured against research diagnosis (Weiser et al., 2005).

[2] 64w Due to safety concerns, in 1998, the MOH has mandated that Clozapine should be prescribed only to patients who have been refractory to two courses of treatment with different antipsychotics. To enforce these guidelines, during 1998 all hospitals were required to report to a national drug registry, linked to the National Psychiatric Hospitalization Case Registry, and monitored by the MOH regarding patient receiving Clozapine.

[3] 82w Israeli law requires that all adolescents between the ages of 16-17 will undergo pre-induction assessment to determine their intellectual, medical and psychiatric eligibility for military service. This assessment is compulsory and is administered to the entire, unselected population of Israeli adolescents. It includes individuals who will be eligible for military service, as well as those who will be excused from service based on medical, psychiatric or social reasons. Data for this study included all adolescents assessed by the Draft Board since 1985.

[4] 52w The Draft Board assessment consists of: (a) a physical examination, review of systems, and psychiatric history all conducted by a physician; (b) an intellectual test battery; and, for males (c) an interview assessing social and behavioral traits. The cognitive and behavioral assessments and their validation are described in detail elsewhere (Gal, 1986).