Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents.

OBJECTIVE: This study reports the results of a prospective, naturalistic treatment study of adolescents considered to be in the prodromal (i.e., prepsychotic) phase of schizophrenia. METHOD: Forty-eight adolescents (mean age = 15.8 years) participating in the initial phase of the Recognition and Prevention (RAP) program (1998-2005) were included in the current report. Individuals were selected from the overall sample (N = 152) if they had: (1) displayed attenuated positive symptoms, (2) been treated pharmacologically for at least 8 weeks, and (3) been followed up for at least 6 months (mean follow-up = 30.5 months). RESULTS: Two types of medication were naturalistically prescribed: antidepressants (N = 20) or second-generation antipsychotics (N = 28), with polypharmacy common. The 2 treatment groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in second-generation antipsychotic-treated adolescents. Twelve of the 48 adolescents (25%) developed a psychotic disorder, with all converters having been prescribed second-generation antipsychotics. There were no conversions among antidepressant-treated adolescents (log-rank chi(2) = 7.36, df = 1, p = .007). Treatment outcome, however, was confounded, since 11 of the 12 converters were nonadherent. Adolescents, in general, were more likely to be nonadherent to second-generation antipsychotics (61%, 17/28) than to antidepressants (20%, 4/20; chi(2) = 7.86, p = .005). Improvement in 3 of 5 positive symptoms over time was significant (p < .001) and similar for both medications. Disorganized thought, however, did not improve regardless of treatment. CONCLUSIONS: Nonrandom assignment limits comparisons between antidepressants and anti-psychotics in this study. However, with follow-up, a number of adolescents meeting criteria for prodromal schizophrenia were successfully treated with antidepressants. At present, a substantial number of false positives among the antidepressant-treated subgroup cannot be ruled out. However, the findings suggest that, in some cases, it might be preferable to begin treatment with antidepressants and progress to antipsychotics once symptoms intensify, since adherence to the latter is difficult to maintain.

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.

Prospective study of adolescents with subsyndromal psychosis: characteristics and outcome.

OBJECTIVE: The aim of this study was to examine the characteristics and outcome of adolescents with psychotic disorder not otherwise specified (PsyNOS) and brief psychotic disorder (BrPsy), two neglected subsyndromal diagnostic entities. METHODS: As part of an ongoing, naturalistic study investigating adolescents considered to be prodromal for schizophrenia, 29 youngsters (mean age, 16.2 +/- 2.7 years) with PsyNOS or BrPsy were identified as theoretically at highest risk for schizophrenia and followed for over 6 (mean, 22.8 +/- 19.4) months. RESULTS: Contrary to our expectations, only 7 of the 26 individuals (27.0%) with follow-up data developed schizophrenia or schizoaffective disorder, and only 2 subjects (7.7%) retained their diagnosis of BrPsy/PsyNOS. The most frequent other diagnoses at follow-up were mood disorders (34.6%), personality disorders (11.5%), and obsessive-compulsive disorder (7.7%). Regarding severity of outcome, 38.5% of the patients progressed to a syndromal psychotic disorder, 23.1% continued to have attenuated positive symptoms, and 38.4% improved to having attenuated negative symptoms only, or no positive or negative symptoms. BrPsy was associated with lower maximum levels of negative symptoms (p = 0.02) and higher likelihood of symptom remission (p = 0.02). CONCLUSIONS: This study indicates that psychotic symptoms not fulfilling criteria for schizophrenia or a psychotic mood disorder are unreliable predictors of a syndromal psychotic disorder outcome at 2 years. Long-term studies of PsyNOS and BrPsy are needed to clarify where these disorders fall in the developmental course of schizophrenia.

Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study.

BACKGROUND: Research suggests that brain frontal white matter (WM) might be qualitatively altered in adolescents with early onset schizophrenia (EOS). Diffusion tensor imaging provides a relatively new approach for quantifying possible connectivity of WM in vivo. METHODS: Diffusion tensor imaging was used to examine the WM integrity of frontal regions at seven levels from 25 mm above to 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. Three other regions were examined: the occipital region at the AC-PC plane and the genu and splenium of the corpus callosum. Fractional anisotropy was compared between 12 adolescents (nine male, 3 female) with EOS (onset of psychotic symptoms by age 18 years) and nine age-similar healthy comparison subjects (six male, 3 female). RESULTS: Adolescents with EOS had significantly reduced fractional anisotropy in the frontal WM at the AC-PC plane in both hemispheres and in the occipital WM at the AC-PC plane in the right hemisphere. CONCLUSIONS: These preliminary data support a hypothesis that alterations in brain WM integrity occur in adolescents with EOS. Abnormalities found in this study were similar to those reported in adults with chronic schizophrenia. Additional studies are needed to assess whether there is progression of WM abnormalities in schizophrenia.

The therapist experience of being the target of hostile versus suspected-unasserted client anger: factors associated with resolution.

The authors qualitatively studied 13 therapists' recollections of 12 hostile and 13 suspected-unasserted client anger events. The trigger for all anger events was a disliked therapist action or inaction. Therapists had more difficulty with hostile than suspected-unasserted client anger. Factors associated with resolution of hostile anger events were a lack of problematic client behaviors, therapists turning negative feelings outward, a goal of connecting with clients, therapists exploring the anger with clients and explaining their behaviors, and therapists conceptualizing the anger as being due to problems in the therapeutic relationship rather than to client personality problems. Factors associated with resolution in suspected-unasserted anger events were a good therapeutic relationship and therapists trying to help clients gain insight and explore the anger. Implications are given for practice and research.

The schizophrenia prodrome revisited: a neurodevelopmental perspective.

Despite the widespread acceptance of the neurodevelopmental model of schizophrenia, its application to research concerned with the prodromal phase of illness is limited. Little recognition has been given to the concept of an enduring biological vulnerability to illness that may be responsive to early intervention. Rather, the focus of most prodromal studies is on emerging positive symptoms. The Recognition and Prevention (RAP) program follows the strategy of being equally concerned with the nonspecific symptoms reflecting the core of schizophrenia and those directly related to psychosis. Data were collected from 62 adolescents (mean age = 16.4 years) during the initial 3-year pilot phase of the RAP program (1998-2001). Subjects were divided into three clinical high-risk groups, characterized by (1) negative and nonspecific symptoms (e.g., social isolation, school failures), the earliest prodrome stage; (2) emerging attenuated positive symptoms of moderate intensity; and (3) severe attenuated (but subpsychotic) positive symptoms, considered most proximal to psychosis. Four risk factors, derived from the neurodevelopmental literature, were selected to reflect the vulnerability core: cognitive deficits, affective disturbances, social isolation, and school failure. All four domains were equally impaired across the three risk groups, supporting the presence of the underlying vulnerability core regardless of the magnitude of emerging positive symptoms. An observational pilot study was also conducted to identify the medications typically used to treat emerging positive symptoms. Antidepressants were used as frequently as antipsychotics to treat adolescents presenting with moderate attenuated positive symptoms. Regardless of type of medication, moderately symptomatic youngsters did quite well over the approximately 1-year followup period. By contrast, adolescents presenting with more severe (but nonpsychotic) attenuated symptoms were treated with antipsychotics, often in combination with other agents. Outcome for the more symptomatic youngsters was, however, more guarded, with nearly half (i.e., 47%) of the group converting to a schizophrenia spectrum psychotic disorder. Nonadherence to medication appeared to be a major risk factor in this group. We conclude that a neurodevelopmental model of schizophrenia is supported by our data and that a range of novel treatment strategies may be neuroprotective by directly affecting the disorder's vulnerability core.