Psychotic Symptom Rating Research Articles

The 22q11.2 Deletion in Children: High Rate of Autistic Disorders and Early Onset of Psychotic Symptoms

To examine psychopathology and influence of intelligence level on psychiatric symptoms in children with the 22q11.2 deletion syndrome (22q11DS). Sixty patients, ages 9 through 18 years, were evaluated. Assessments followed standard protocols, including structured and semistructured interviews of parents, videotaped psychiatric interview, and intelligence assessment of the child. Intelligence level, psychiatric symptoms, and classification provided the main outcome. High rates of autism spectrum disorders (30 of 60, 50.0%) and psychotic symptoms (16 of 60, 26.7%) were found in this sample. In 7 of 60 (11.7%), the psychotic symptoms interfered with behavior and caused considerable distress. In these cases, the diagnosis of a psychotic disorder was applied. The average age of the children with psychotic symptoms at time of assessment was 14.2 years. Although it is likely that the high rate of psychopathology in this sample is to some extent associated with the lower level of cognitive function, a major effect of the degree of cognitive impairment on psychiatric morbidity was not found. Autism spectrum disorders and subthreshold autistic symptomatology are common in children with 22q11DS. Furthermore, a high rate of psychosis and psychotic symptoms is found in this childhood sample, suggesting an early onset of psychosis in 22q11DS patients. Autistic and psychotic disorders should be considered to be main elements of the behavioral phenotype of 22q11DS children.

Left superior temporal gyrus activation during sentence perception negatively correlates with auditory hallucination severity in schizophrenia patients

The left superior temporal cortex, which supports linguistic functions, has consistently been reported to activate during auditory–verbal hallucinations in schizophrenia patients. It has been suggested that auditory hallucinations and the processing of normal external speech compete for common neurophysiological resources. We tested the hypothesis of a negative relationship between the clinical severity of hallucinations and local brain activity in posterior linguistic regions while patients were listening to external speech. Fifteen right-handed patients with schizophrenia and daily auditory hallucinations for at least 3 months were studied with event-related fMRI while listening to sentences in French or to silence. Severity of hallucinations, assessed using the auditory hallucination subscales of the Psychotic Symptom Rating Scales (PSYRATS) and of the Scale for the Assessment of Positive Symptoms (SAPS-AH), negatively correlated with activation in the left temporal superior region in the French minus silence condition. This finding supports the hypothesis that auditory hallucinations compete with normal external speech for processing sites within the temporal cortex in schizophrenia.

Evidence that the urban environment specifically impacts on the psychotic but not the affective dimension of bipolar disorder

High rates of psychotic disorders and psychotic symptoms have been found in urban environments but reports for bipolar affective illness have been inconsistent, possibly due to failure to stratify for comorbid psychotic symptoms. It was hypothesised, therefore, that any effect of urbanicity on the bipolar phenotype would be moderated by comorbid psychotic symptoms. In a random, representative population cohort of 7049 adults with no history of non-affective psychotic disorder, the cumulative incidence of bipolar and psychotic symptoms and syndromes, assessed with the CIDI, was examined over five levels of population density of place of residence. Similarly, the degree of comorbidity between broadly and narrowly defined bipolar phenotypes on the one hand, and the dichotomous presence of broadly (17.2%) and narrowly defined (3.8%) psychotic symptoms on the other, was examined as a function of population density of place of residence. The rate of bipolar disorder, however defined, was progressively higher in more urbanised areas. However, in models of bipolar phenotypes, a strong interaction between comorbid psychosis and level of urbanicity was apparent, indicating that the greater the degree of psychotic comorbidity, the greater the effect size of the urban environmental factor. For bipolar disorder without psychosis, no effect of urbanicity was apparent. The results suggest differential environmental causal effects on affective and cognitive dimensions of bipolar psychopathology that are nevertheless strongly comorbid within the same categorically defined disorder, possibly due to the effect of shared genetic risk factors.

Psychotic symptoms in patients undergoing coronary artery bypass grafting and heart valve operation

Delirium on internal medicine and surgical wards of the general hospital is associated with several predisposing and precipitating factors as well as adverse outcomes. Whether psychosis, the symptom of delirium that may be recognized most promptly, is similarly associated with these factors and outcomes is largely unknown. Eight thousand one hundred and thirty-nine consecutive patients undergoing coronary artery bypass grafting and/or heart valve operation were screened for preoperative predisposing factors and postoperative psychotic symptoms between January 1999 and July 2004. Data on per- and postoperative precipitating factors were collected in 4942 patients enrolled between January 2001 and July 2004. Data were examined using logistic regression to estimate odds ratios. The rate of severe psychotic symptoms was 2.1% (n=168). Higher age, renal failure, dyspnoea, heart failure, and left ventricle hypertrophy were independent preoperative predisposing factors. Peroperative hypothermia (<33 degrees C), hypoxemia, low hematocrit, renal failure, increased sodium, infection and stroke were independent precipitating factors. Psychotic symptoms were independently associated with a prolonged length of stay on the intensive care unit (odds ratio 7.8; 95% confidence interval 5.6-11), multi-organ failure or shock (3.2; 95% CI: 2.2-4.9), cardiopulmonary resuscitation (3.6; 95% CI: 2.1-6.2), and in-hospital death after surgery (2.1; 95% CI: 1.1-4.1). Psychotic symptoms are independently associated with several chronic and peroperative problems (including mild hypothermia during surgery), closely resembling those for delirium (with and without psychotic symptoms). Psychotic symptoms are also independently associated with adverse outcomes. Prompt diagnostic and therapeutic intervention aimed at the underlying problem may improve outcomes.

Treating Auditory Hallucinations by Transcranial Magnetic Stimulation: A Randomized Controlled Cross-Over Trial

Background: In a previous functional magnetic resonance imaging study, the authors succeeded in demonstrating the activation of Heschl’s gyrus during auditory hallucinations (AH). Objectives: This study aims to treat AH specifically by repetitive transcranial magnetic stimulation (rTMS). Methods: 16 patients with AH were included in a randomized, cross-over, sham-controlled trial. 1 Hz rTMS was administered over the left and right temporo-parietal cortex and sham position, respectively, on 5 consecutive days; 900 stimuli each, strength 100% of motor threshold. Using the Psychotic Symptom Rating Scales (PSYRATS), the hallucinations during the stimulation periods and 4-week follow-ups were quantified. Electroencephalograms (EEG) were acquired before and after each period. Results: Treatment responses were observed after left hemisphere rTMS only. The 5 patients who showed a response did so already after 2 days. However, group mean hallucination scores did not differ across treatment conditions. No significant changes were found in EEG after rTMS. Conclusions: A subgroup of patients suffering from AH benefits soon after treatment start from rTMS over the left superior temporal gyrus as revealed by the decrease of AH scores compared to right-sided and sham procedures.

Persistent Auditory Hallucinations

Background: There is still a significant proportion of psychotic patients who suffer from persistent auditory hallucinations (PAH) in spite of treatment. The objective of our study was to analyze those clinical dimensions that characterize persistent hallucinators in comparison with episodic hallucinators. Sampling and Methods: Ninety-one outpatients with AH were assessed through semistructured interviews. The interviews included the Psychotic Symptom Rating Scales for AH and the Krawiecka scale. They elicited descriptions about the persistence of AH, existence of pleasurable hallucinations and other types of hallucinations. Results: Forty-five patients fulfilled criteria for reported PAH. Persistent hallucinators showed greater scores in frequency and duration of hallucinations, Krawiecka total score and incoherence of speech. Moreover, pleasurable experiences were more frequent in this group of patients. Logistic regression analysis rendered a model with the following variables: duration of voices, degree of control and pleasurable hallucinations. Conclusion: Specific dimensions of AH can predict the possibility of treatment resistance.

Evidence that the outcome of developmental expression of psychosis is worse for adolescents growing up in an urban environment

The urban environment may increase the risk for psychotic disorder in interaction with pre-existing risk for psychosis, but direct confirmation has been lacking. The hypothesis was examined that the outcome of subclinical expression of psychosis during adolescence, as an indicator of psychosis-proneness, would be worse for those growing up in an urban environment, in terms of having a greater probability of psychosis persistence over a 3.5-year period. A cohort of 918 adolescents from the Early Developmental Stages of Psychopathology Study (EDSP), aged 14-17 years (mean 15.1 years), growing up in contrasting urban and non-urban environments, completed a self-report measure of psychotic symptoms at baseline (Baseline Psychosis) and at first follow-up around 1 year post-baseline (T1). They were again interviewed by trained psychologists for the presence of psychotic symptoms at the second follow-up on average 3.5 years post-baseline (T2). The rate of T2 psychotic symptoms was 14.2% in those exposed to neither Baseline Psychosis nor Urbanicity, 12.1% in those exposed to Urbanicity alone, 14.9% in those exposed to Baseline Psychosis alone and 29.0% in those exposed to both Baseline Psychosis and Urbanicity. The odds ratio (OR) for the combined exposure was 2.46 [95% confidence interval (CI) 1.46-4.14], significantly greater than that expected if Urbanicity and Baseline Psychosis acted independently. These findings support the suggestion that the outcome of the developmental expression of psychosis is worse in urban environments. The environment may impact on risk for psychotic disorder by causing an abnormal persistence of a developmentally common expression of psychotic experiences.

The reliability and validity of general psychotic rating scales with people with mild and moderate intellectual disabilities: an empirical investigation

Whilst assessment tools have been developed to diagnose schizophrenia in people with mild intellectual disabilities (IDs), little attention has been paid to developing reliable and valid dimensional measures of psychotic experiences with this population. This study investigates the reliability and validity of two such measures developed for the general adult psychiatric population, the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scales (PSYRATS), with a population of adults with mild IDs. Sixty-two adults with mild IDs were interviewed using the PANSS and PSYRATS, and independently interviewed using the Psychiatric Assessment Schedule--Adults with Developmental Disability (PAS-ADD) to obtain psychiatric diagnoses to the criteria of the International Classification of Diseases--Tenth Revision (ICD-10). On the basis of ICD-10 diagnosis, participants were divided into three groups: psychosis (n=11); other mental health problem (n=14); no mental health problem (n=37). PANSS and PSYRATS subscale scores were compared across these three groups and were correlated with PAS-ADD symptom scores across a number of PAS-ADD symptom domains. All PANSS and PSYRATS subscales showed adequate internal reliability, largely good test-retest reliability, and logical inter-correlations between subscales. The PANSS positive symptoms and the PSYRATS auditory hallucinations subscales differentiated between the psychosis group and the other groups; the PANSS general symptoms subscale differentiated between the psychosis and no mental health problem groups; and the PANSS negative symptoms and the PSYRATS delusions subscales did not differentiate between the three groups. The PANSS and PSYRATS are promising measures for use with people with mild IDs and psychotic experiences, although further investigation of items relating to negative symptoms and delusions is warranted.

Psychotic symptoms in the general population of England

There is considerable evidence that incidence of schizophrenia and other psychoses varies across ethnic groups in the UK, with particularly high rates for people of African-Caribbean origin. The aims of this shady were to estimate in a community-based sample of people from ethnic minorities: 1) the prevalence of psychotic symptoms; and 2) risk factors for reporting psychotic symptoms. Face-to-face interviews were carried out with a probabilistic sample of 4281 adults from six ethnic groups living in the UK. Psychotic symptoms were measured using the psychosis screening questionnaire (PSQ). There was a twofold higher rate of reporting psychotic symptoms on the PSQ in Black Caribbean people compared with Whites. Adjustment for demographic factors had little effect on this association. Prevalence rates of psychotic symptoms were higher in people from ethnic minorities, but were not consistent with the much higher first contact rates for psychotic disorder reported previously, particularly in Black Caribbeans.

MIRKEN REFUTED: REASONS FOR BELIEVING THAT THE ASSOCIATION BETWEEN CANNABIS USE AND RISK OF PSYCHOSIS IS PROBABLY CAUSAL

In his comment on our research, Mirken [1] suggests that our conclusions that ‘our findings add to the growing body of evidence that regular cannabis use may increase risks of psychosis’ can be explained by the fact that ‘the case for marijuana causing mental illness is based solely on marijuana smokers having the completely reasonable feelings that they have different beliefs from mainstream society . . .’. These arguments succeed only by virtue of Mirken ignoring most of the body of evidence to which we refer. In particular, it has been well established by longitudinal studies that the heavy use of cannabis is associated with increased rates of both psychosis [2, 3] and psychotic symptoms [4-8]. This consistent finding using different approaches to assessing psychosis and psychotic symptoms makes it very difficult to claim that the link between cannabis and psychosis/psychotic symptoms simply reflects the fact that cannabis users have different beliefs from the rest of society. In his specific critique of our research Mirken raises two general issues. First, it is proposed that any increase in paranoid symptoms amongst cannabis users may reflect the effects of legislation which justifies cannabis users being ‘a tad suspicious of others’ or ‘feeling other people cannot be trusted’. However this argument is not consistent with the evidence on this topic, since linkages between cannabis and psychosis/psychotic symptoms have been found in societies which have both liberal and conservative policies towards cannabis. Thus, findings from New Zealand [4-6] where cannabis use is illegal have been similar to those from Holland [8], which has more liberal legislation. These comparisons suggest that it is implausible to propose that increased rates of psychotic symptoms amongst cannabis users reflect the impacts of cannabis legislation on the belief system of users. Second, it is suggested that the associations between cannabis and psychosis/psychotic symptoms may simply reflect reports of the acute effects of cannabis use. This argument has merit given the evidence that acute cannabis intoxication may mimic the symptoms of psychosis [9]. Mirken claims that it was necessary for our research to distinguish these short-term effects from longer-term effects by ascertaining whether the symptoms occurred in the context of cannabis use. A little reflection on our research analysis reveals the difficulties of this proposal. In particular, the focus of the analysis was on weekly and daily users of cannabis. Given this high frequency of use it would have been difficult, if not impossible, for the respondents to identify the times of the day in which they were experiencing acute symptoms and the times of the day they experienced longer-term symptoms. However, the power of a longitudinal design is that it has the capacity to examine both short- and long–term associations. This capacity is used in Table 1 below which examines the linkages between cannabis use at ages 17–18 and levels of psychotic symptoms at ages 18, 21 and 25. This table shows that linkages between cannabis use and psychotic symptoms persist for up to seven years. In passing, we note that a recently published paper by Henquet et al. [7] reports associations over a four year period. This association between cannabis use and long-term psychotic symptoms clearly argues against the view that the association is due to cannabis users reporting acute symptoms of cannabis intoxication. In summary, the arguments proposed by Mirken fail on three grounds. First, these arguments disregard the growing body of evidence showing linkages between cannabis use and psychosis/psychotic symptoms assessed in a variety of ways and in a range of social contexts. Second, cross-cultural comparisons suggest that it is highly unlikely that these associations reflect the responses of cannabis users to legislation, since the associations exist in societies with both liberal and conservative attitudes. Finally, evidence from recent studies suggests linkages between cannabis use and psychosis/psychotic symptoms persist over a lengthy period of time implying that it is highly unlikely that these associations reflect reports of the acute effects of cannabis intoxication.

Tests of causal linkages between cannabis use and psychotic symptoms

To examine possible causal linkages between cannabis use and psychosis using data gathered over the course of a 25-year longitudinal study. A 25-year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children (635 males, 630 females). The Christchurch Health and Development Study, a general community sample. A total of 1055 participants from the Christchurch Health and Development Study (CHDS) cohort for whom data on cannabis use and psychotic symptoms were available on at least one occasion from 18, 21 and 25 years. As part of this study, data were gathered on frequency of cannabis use and psychotic symptoms at ages 18, 21 and 25 years. Regression models adjusting for observed and non-observed confounding suggested that daily users of cannabis had rates of psychotic symptoms that were between 1.6 and 1.8 times higher (P < 0.001) than non-users of cannabis. Structural equation modelling suggested that these associations reflected the effects of cannabis use on symptom levels rather than the effects of symptom levels on cannabis use. The results of the present study add to a growing body of evidence suggesting that regular cannabis use may increase risks of psychosis. The present study suggests that: (a) the association between cannabis use and psychotic symptoms is unlikely to be due to confounding factors; and (b) the direction of causality is from cannabis use to psychotic symptoms.

Psychotic symptoms among male adolescent detainees in The Netherlands.

This study investigated the prevalence of psychotic symptoms among incarcerated boys as well as the relationship between these symptoms and violent offending and criminal recidivism. The presence of psychotic symptoms was assessed in a representative sample of 204 incarcerated boys aged 12-18 using the Diagnostic Interview Schedule for Children (DISC-2.3). Seventy-two percent of the study participants had committed a violent index offense and 30 percent were criminal recidivists. Thirty-four percent (95% confidence interval [CI]: 27-41%) were DISC-2.3 psychosis screen positive: 25% (95% CI: 19-31%) reported at least one pathognomonic of schizophrenia symptom and 9% (95% CI: 6-14%) reported at least three non-pathognomonic psychotic symptoms. In addition, 33 percent (95% CI: 26-40%) reported one or two isolated, atypical psychotic symptoms. The presence of psychotic symptoms was not associated with violent offending or criminal recidivism. The high prevalence rate of psychotic symptoms among incarcerated boys calls for increased attention to diagnosis and treatment of psychosis. To obtain conclusive answers regarding the relationship between psychosis and violent offending, additional studies are needed in general population samples.

Neuroticism in adolescence and psychotic symptoms in adulthood.

The aims of this research were to examine the associations between the personality trait of neuroticism in adolescence and later psychotic symptoms, taking into account potential confounding factors. Data were gathered over the course of a longitudinal study of a birth cohort of New Zealand born young people (N=1265). Over the course of the study, data were gathered on: (a) neuroticism at age 14; (b) psychotic symptoms predominantly subclinical, assessed on the Symptom Checklist (SCL-90), at ages 18 and 21; (c) a range of potential confounding factors including measures of childhood adversity and co-morbid mental disorders. Young people in the highest quartile of neuroticism at age 14 had rates of psychotic symptoms that were two to three times higher than those in the lowest quartile. After statistical adjustment for confounding factors, including childhood adversity and co-morbid mental disorders, the association between neuroticism and later psychotic symptoms reduced but remained statistically significant (P<0.05). After adjustment for confounding, young people with high levels of neuroticism had rates of psychotic symptoms that were between 1.5 to 1.8 times higher than those with low levels of neuroticism. Early neuroticism may be a precursor to the onset of psychotic symptoms. The mechanisms underlying this association are unclear, but may relate to overlapping features between prodromal phases of psychosis and items that measure neuroticism.

The functional anatomy of forgiveness in patients with schizophrenia

The left superior temporal cortex, which supports linguistic functions, has consistently been reported to activate during auditory–verbal hallucinations in schizophrenia patients. It has been suggested that auditory hallucinations and the processing of normal external speech compete for common neurophysiological resources. We tested the hypothesis of a negative relationship between the clinical severity of hallucinations and local brain activity in posterior linguistic regions while patients were listening to external speech. Fifteen right-handed patients with schizophrenia and daily auditory hallucinations for at least 3 months were studied with event-related fMRI while listening to sentences in French or to silence. Severity of hallucinations, assessed using the auditory hallucination subscales of the Psychotic Symptom Rating Scales (PSYRATS) and of the Scale for the Assessment of Positive Symptoms (SAPS-AH), negatively correlated with activation in the left temporal superior region in the French minus silence condition. This finding supports the hypothesis that auditory hallucinations compete with normal external speech for processing sites within the temporal cortex in schizophrenia.

Racial differences in psychotic symptoms among combat veterans with PTSD.

We tested the hypothesis that race may influence clinical presentation and symptomatology in combat veterans with posttraumatic stress disorder (PTSD). African-American and Caucasian veterans were administered the Psychotic Screen Module of the Structured Clinical Interview for DSM, Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and other psychometric measures at a Veterans Affairs outpatient PTSD clinic. Subjects were consecutive referrals who were not matched for level of combat trauma or preexisting trauma; however, there were no group differences in other relevant demographic or diagnostic variables. Significant racial differences, with modest effect sizes, were found on clinician ratings of psychotic symptoms, MMPI-2 scale 6 ("paranoia"), and a measure of dissociation. No significant differences were found for the MMPI-2 scale 8 ("schizophrenia"), or on measures that might suggest comorbid depression or anxiety. African-Americans with PTSD endorsed more items suggesting positive symptoms of psychosis, without higher rates of primary psychosis, depression, or anxiety than Caucasians.

Double-Blind Antiglucocorticoid Treatment in Schizophrenia and Schizoaffective Disorder: A Pilot Study

Summary: Background: Antiglucocorticoids, such as ketoconazole, have been investigated as antidepressant agents in major depression and other conditions. Despite evidence that a significant number of patients with schizophrenia and schizoaffective disorder are both hypercortisolemic and depressed, the antidepressant effects of antiglucocorticoids have never been assessed in these populations.Methods: Fifteen symptomatic patients with diagnoses of schizophrenia or schizoaffective disorder, who were at least partially treatment-resistant, were treated with ketoconazole, up to 800 mg/day, (n = 8) or placebo (n = 7) for four weeks in a double-blind manner. The study medication was added to a pre-stabilized antipsychotic and/or antidepressant medication regimen.Results: Ketoconazole treatment, compared to placebo, was associated with significant improvements in observer-rated depression, but not in subjectively rated depression, positive or negative psychotic symptom ratings, or cognitive performance scores.Conclusions: These pilot data partially support the hypothesis that antiglucocorticoids reduce depressive symptoms in patients with schizophrenia and schizoaffective disorder, although objective and subjective ratings may not be similarly affected during a four-week course of treatment. Further studies with larger sample sizes, more extensive endocrine assessments and longer duration of drug administration seem warranted.

Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia.

Knowledge of the relationship between specific cognitive abnormalities and the clinical symptoms of schizophrenia could give insight into the nature of their underlying pathophysiology. Composite scores were generated for negative, disorganized, and psychotic symptom ratings in 134 patients with schizophrenia (DSM-IV criteria). Partial correlations (each composite corrected for the others) were computed with neuropsychological measures. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing. Disorganized symptoms were correlated with lower verbal IQ and poor concept attainment. Psychotic symptoms had no significant relationship with cognitive deficit.

Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS).

Scales to measure the severity of different dimensions of auditory hallucinations and delusions are few. Biochemical and psychological treatments target dimensions of symptoms and valid and reliable measures are necessary to measure these. The inter-rater reliability and validity of the Psychotic Symptom Rating Scales (PSYRATS: auditory hallucination subscale and delusions subscale), which measure several dimensions of auditory hallucinations and delusions were examined in this study. The two scales were found to have excellent inter-rater reliability. Their validity as compared with the KGV scale (Krawiecka et al. 1977) was explored. It is concluded that the PSYRATS are useful assessment instruments and can complement existing measures.

Psychotic subtyping of major depressive disorder and posttraumatic stress disorder.

Many studies have established that a large percentage of patients with posttraumatic stress disorder (PTSD) have comorbid major depressive disorder. Other studies have found that patients with PTSD or a history of childhood trauma have an increased rate of psychotic symptoms. In the present report from the Rhode Island Methods to Improve Diagnosis and Services project, we examine whether an association exists between psychotic subtyping of major depressive disorder and PTSD. Five hundred psychiatric outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Almost half of the 500 patients had nonbipolar major depressive disorder (N = 235, 47.0%), 45 (19.1%) of whom had PTSD. Nineteen patients had psychotic depression, 216 had nonpsychotic depression. Compared with patients with nonpsychotic depression, the patients with psychotic depression were nearly 4 times more likely to have PTSD (57.9% vs. 15.7%, Fisher exact test, p = .0001). The results of the present study suggest that the presence of psychosis in psychiatric outpatients with major depressive disorder is associated with concurrent PTSD. It is hypothesized that the poorer longitudinal course of psychotic versus nonpsychotic depression may be due to the underrecognition of PTSD in psychotically depressed patients.

A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia

Background: d-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine. Methods: Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of d-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout. Results: Eleven patients competed the 13-week study. d-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms. Conclusions: The differing effects of d-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapine’s efficacy for negative symptoms.