Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder.

This study investigated adolescent cannabis use as a risk factor for schizophrenia spectrum disorder (SSD). Motives for early cannabis use and resulting usage patterns were examined alongside clinical measures of SSD onset and symptomatology. Participants (N = 178) were recruited for two samples, 1: healthy controls (HC) with cannabis use, 2: schizophrenia patients (SSD) with cannabis use. Structured interviews of participants and family informants were used to obtain diagnostic and biographical information. Factor-analysis of reported motives for initiating cannabis use produced four groups; sedation, stimulation, social pressure, and recreation. Regression analyses revealed significant relationships between these groups and SSD. Most notably, reason group factor scores predict SSD risk as well as schizotypal symptom severity. Findings also indicate that these factors follow a hierarchical structure, which explains their relative involvement in increased SSD risk. We suggest that adolescent cannabis use both hastens the onset and amplifies the severity of SSD. In response we propose a model for identifying at risk individuals, predicting the onset and severity of SSD, and potentially mitigating the associated psychiatric impairments.

Less is more Redux: Scheduled intermittent dosing to protect/prevent cognitive deterioration in schizophrenia.

We propose a strategy of scheduled intermittent dosing in place of daily administration of antipsychotic medications for the treatment of patients with schizophrenia. Intermittent (extended) dosing has already been demonstrated to be at least equally effective as daily administration of antipsychotic medications. It is increasingly appreciated that remission of positive symptoms is not the same as recovery: a resumption of a productive and socially gratifying life. Our field has focused on positive symptoms to the exclusion of cognitive deterioration and emotional blunting. Dopamine is the primary neurotransmitter responsible for the accumulation and processing of new information as well as the expression of emotions modulated via the nucleus accumbens. Data suggests that patients receiving less accumulated antipsychotic agents do better over the years in achieving meaningful recoveries. In addition to clinical improvement, there is the financial benefit in giving less medication, which is often costly, over several decades. Finally, there is the possibility, albeit not yet demonstrated, that less accumulated antipsychotic agents might reduce the occurrence of significant weight gain, the metabolic syndrome, with its accompanying medical complications which not only impacts the quality of life and life expectancy of those who suffer from it, but also increases the financial burden to society.

Impaired motor performance in adolescents at familial high-risk for schizophrenia.

BACKGROUND: The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. METHODS: Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. RESULTS: FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. CONCLUSIONS: The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.

Can P300 distinguish among schizophrenia, schizoaffective and bipolar I disorders? An ERP study of response inhibition.

Research utilizing visual event-related brain potentials (ERPs) has demonstrated that reduced P300 amplitude and prolonged latency may qualify as a biological marker (biomarker) for schizophrenia (SZ). We examined P300 characteristics in response inhibition among three putatively distinct psychopathology groups including schizophrenia (SZ), bipolar I disorder (BD) and schizoaffective disorder (SA) in comparison with healthy controls (CT) to determine their electrophysiological distinctiveness. In two separate studies, deficits in response inhibition indexed by the P300 component were investigated using a lateralized Go/NoGo task. We hypothesized that deficits in response inhibition would be present and distinctive among the groups. In both studies, SZ showed response inhibition deficits as measured by P300 when stimuli were presented to the right visual field. In Study 2, delayed cognitive stimulus evaluation was observed in BD as indexed by prolonged P300 latency for NoGo trials. Six selected NoGo P300 variables out of thirty six NoGo P300 variables (18 amplitude, 18 latency) correctly classified SZ (79%), SA (64%) in Study 1 and seven variables selected in Study 2 classified CT (80%), and SZ (61%), BD (67%) and CT (68%) with the accuracy higher than chance level (33%). The findings suggest that distinct P300 features in response inhibition may be biomarkers with the capacity to distinguish BD and SZ, although SA was not clearly distinguishable from SZ and CT.

Altered language network activity in young people at familial high-risk for schizophrenia.

BACKGROUND: Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first-degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. METHODS: Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. RESULTS: There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. CONCLUSIONS: FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder.

Frequency of normative word associations in the speech of individuals at familial high-risk for schizophrenia.

The intrusion of associations into speech in schizophrenia disrupts coherence and comprehensibility, a feature of formal thought disorder referred to as loosened associations. We have previously proposed that loosened associations may result from hyperactivity in semantic association networks, leading to an increased frequency of associated words appearing in speech. Using Computed Associations in Sequential Text (CAST) software to quantify the frequency of such associations in speech, we have reported more frequent normative associations in language samples from patients with schizophrenia and in individuals with schizotypal characteristics. The present study further examined this deviance in schizophrenia by studying normative associations in those who share genes with an individual with schizophrenia, (i.e. first-degree relatives of probands with schizophrenia; HR) but who do not have an illness. Familial high-risk participants (n=22), and controls (n=24) provided verbal responses to cards from the Thematic Apperception Test. CAST analysis revealed that HR used more associated words in their speech compared to controls. Furthermore, the frequency of normative word associations was positively correlated with dimensional and total scores of schizotypy derived from ratings of the structured interview for schizotypy, which confirms past research showing a relationship between schizotypy and hyperassociations. Our results suggest that some language disturbances in schizophrenia likely arise from an underlying psychopathological mechanism, hyperactivity of semantic associations.

Initiation of clozapine therapy in a patient with preexisting leukopenia: a discussion of the rationale of current treatment options.

Clozapine remains the most effective agent for diminishing or eliminating psychotic symptoms in treatment-resistant patients. However, among such patients, a small percentage (<3.0%) develops clozapine-induced granulocytopenia (CIG). In spite of the fact that lithium and granulocyte colony stimulating factor (G-CSF) have been shown to reverse CIG, many such patients are consigned to treatment with antipsychotic agents that have failed in the past. Apparently, their physicians are not aware that these patients can be salvaged for ongoing clozapine treatment. We report the effectiveness of lithium in reversing CIG in a young man with preexisting mild granulocytopenia. The rapidity of onset of leukocyte depletion is discussed in light of previously hypothesized autoimmune mechanisms of CIG. This case dramatizes the importance of lithium (or G-CSF) augmentation in those patients to maintain clozapine treatment so that their neutropenia can be reversed, and they can continue to benefit from the unique antipsychotic qualities of clozapine.

Age disorientation in schizophrenia: an indicator of progressive and severe psychopathology, not institutional isolation.

The authors investigated age disorientation in chronic schizophrenia to determine whether specific symptomatic, neurologic, and cognitive disturbances were linked to its presentation. Disorientation to their age was detected in 30% (16/54) of the schizophrenic patients in a chronic care facility. In matched comparisons, age-disoriented patients showed lower educational achievement, poorer mental state performance, and a greater severity of symptoms, as well as more severe motor and sensory impairments. Levels of social withdrawal did not differentiate the two groups. A two-hit model consistent with neurodevelopmental and neurodegenerative processes is proposed to explain the data.

Impaired verbal memory is associated with impaired motor performance in schizophrenia: relationship to brain structure.

Deficient ability to take advantage of predictable elements in the performance of cognitive tasks has been proposed as an underlying factor for a number of deviances in schizophrenia. In a schizophrenic sample (n=39), we propose and test the view that certain memory and motor anomalies arise because of a compromise in the capacity to take advantage of the redundant (predictable) features of cognitive tasks. Results demonstrate a relationship between reduced capacity to take advantage of predictable features of two different cognitive processing tasks, one verbal memory, and the other motor. Poorer verbal recall on high-redundancy word lists was associated with a reduced ability to produce synchronous finger tapping in response to a high redundancy auditory stimulus, and inversely correlated with formal thought disorder ratings. These relationships, we suggest, reflect a specific and common schizophrenic deficit in the use of redundancies, not attributable to a generalized deficiency in performance. Structural imaging evidence from a subsample of these subjects (n=16) implicates frontal areas as the locus of this cognitive impairment.

Effects of clozapine on psychiatric symptoms, cognition, and functional outcome in schizophrenia.

This study focused on the symptomatic and cognitive effects of the atypical antipsychotic clozapine in chronic hospitalized schizophrenia patients. Further, it explored how these effects might be related to discharge, an important functional outcome. Patients were assessed at baseline and at regular intervals with clinical instruments and a cognitive battery. Clozapine treatment produced symptomatic and cognitive improvements, positive changes that appeared to occur independently of one another. Baseline cognitive performance, as well as cognitive change with treatment, predicted discharge. Further investigation of the effects of clozapine and other atypical antipsychotics on cognition and functional outcome is warranted.

Hemispheric asymmetry of frontal and temporal gray matter and age of onset in schizophrenia.

BACKGROUND: Investigators have reported lack of normal asymmetry of lateralization in some schizophrenic patients, as measured postmortem and by preference and/or performance. It has been suggested that this lack of asymmetry is related to early onset of schizophrenia. The present study extends the inquiry by magnetic resonance imaging (MRI) measurement of volumetric asymmetry. METHODS: Hemispheric asymmetry of volume in regional gray matter was examined in 16 schizophrenic patients who had undergone MRI of brain volume. RESULTS: Low levels of hemispheric asymmetry in the frontal and temporal areas were strongly associated with early onset of schizophrenia, the association with frontal volume being more marked than with temporal volume. No relationship was found in the other brain areas that were scanned. The findings were not artifacts of chronological age, nor of extreme scores in a small sample. CONCLUSIONS: These findings are consistent with the hypothesis that failure to develop asymmetry is an important component of the pathology underlying some forms of schizophrenia.

Hemispheric specialization in schizophrenics with perceptual aberration.

Higher rates of left-handedness and atypical lateralization in schizophrenics paired with findings of morphological abnormalities in cerebral asymmetry suggest that the normal patterns of hemisphere specialization for processing verbal and spatial information may be anomalous in schizophrenics. The small number of studies that have addressed this question have produced inconsistent findings and varied with subtype diagnosis, gender, type of task employed, task difficulty, and control of handedness. Conflicting research findings also may be due to confounding from the heterogeneity of the schizophrenic construct and variability in clinical symptoms across patients. The present study was designed to control for factors that may have confounded earlier studies. Because the study used perceptual measures, the relationship between symptoms of perceptual aberration and hemisphere advantages was examined using Chapman et al.'s (1978) Perceptual Aberration Scale (PAS). Fifteen male schizophrenic patients and 14 male controls were administered tachistoscopic letter and facial recognition go/no-go reaction time tasks. Left hemisphere advantages were found for both controls and schizophrenics on the letter task. Right hemisphere advantages were found for controls on the facial task but not schizophrenics. Instead, a strong negative correlation was found between schizophrenics' PAS scores and hemisphere advantages (r = -0.685, p < 0.007). Further analysis identified a subgroup of schizophrenics with perceptual aberration who exhibited reversed left hemisphere advantages that increased as the PAS scores increased. Additional research is needed to determine whether this subgroup of schizophrenics constitutes a meaningful subtype with a distinct disease process that disrupts the development of normal cerebral lateralization. The findings provide further evidence for the importance of examining relationships between schizophrenics' performance on cognitive measures and their symptom patterns.

Context memory in schizoaffective and schizophrenic disorders.

DSM IV preserves the boundary between schizoaffective disorder and schizophrenia, yet validation of the former condition remains incomplete. The prevalent view that schizoaffective disorder is a less serious condition than schizophrenia suggest that cognitive disturbance might be less severe and possibly different from that found in schizophrenia. We investigated a well-characterized cognitive difficulty in schizophrenia, the relative lack of gain in verbal recall when context is increased, in samples of patients and normal controls. Subjects with schizophrenia (n = 19) were individually matched for age, sex, and recall performance with patients diagnosed with schizoaffective disorder (n = 19) and major depression (n = 19); and with normal controls (n = 19). Patients were also matched on duration of illness. The results indicate that schizophrenic subjects attain smaller gains in recall when context is increased compared to depressed and normal controls, a finding consistent with previous results. Schizophrenic and schizoaffective subjects, however, did not differ in recall gain on this task. We conclude that schizoaffective subjects cannot be distinguished from schizophrenic subjects on this cognitive feature.

Line drawing as a possible measure of lateralized motor performance in schizophrenia.

In this paper we suggest a new method, conceived by Maher, to assess lateralized motor performance in schizophrenia. Subjects draw two straight lines with each hand. The lines are scanned into a computer, and a regression is run on the points of the line. The root mean squared error (RMS) of the regression equation indicates the deviation from straightness of the line. The average RMS of all four lines is taken as an overall measure of motor disorder, and the difference in performance between the two hands serves as an index of motoric laterality. Scores on the motor disorder index were significantly positively related to clinical ratings of Parkinsonism among schizophrenic inpatients. A marginal relation was found to ratings of voluntary movement disorders, and the task was not associated with dyskinetic movements. Scores on the motor disorder measure were significantly worse for schizophrenic subjects than for staff controls. The laterality index significantly differentiated right- and left-handed subjects, but did not differentiate schizophrenic from control subjects. Maher's simple line drawing task yields objective continuous ratings of motor disorder and handedness and may be a useful tool for examining associations between motor functioning and cognition and symptomatology in schizophrenia.

Length of illness and the gradient from positive to negative semantic priming in schizophrenic patients.

Schizophrenic patients, especially those with positive thought disorder, have been shown to show greater facilitation in a semantic priming task than normal controls and depressed patients. While some investigators have replicated these effects, others have not been able to do so. Differences in method and in the chronicity of the patients make it difficult to interpret the discrepancy between findings. The present study was conducted to examine the effect of length of illness (LOI) on semantic priming, a factor that might explain differences in replication success. Thirty schizophrenic patients performed a lexical decision task in a semantic priming paradigm. The LOI of this group ranged from 5 to 31 years. Facilitation in the priming task was positive for patients with short LOIs and declined to negative values in patients with long LOIs. The gradient of decline was significant. Analysis of the separate components of facilitation indicates that the decline was primarily due to a steady reduction of the speed with which patients responded to the associated word pairs; speed of response to non-associated pairs was unaffected. As this was a cross-sectional study it is not possible to determine whether the decline can be attributed to a cumulative effect of length of illness, or to prior initial differences in pathology that affect the probability of chronicity.

Delusional disorder: the recognition and management of paranoia.

Delusional disorder, the contemporary conceptualization of paranoia, is an uncommon condition characterized by the presence of one or more nonbizarre delusions and the relative absence of associated psychopathology. The delusions concern experiences that can conceivably occur in real life, such as being followed (persecutory type), having a disease (somatic type), being loved at a distance (erotomanic type), having an unfaithful sexual partner (jealous type), and possessing inflated worth, power, identity, or knowledge (grandiose type). The diagnosis requires at least 1 month's duration of the delusion; impact on functioning that is consistent with the delusion or its ramifications; generally normal appearance and behavior; and the exclusion of schizophrenia, mood disorder, substance-induced toxicity, and medical disease. Typically, patients are unaware of the psychiatric nature of the condition. They may present to internists, dermatologists, plastic surgeons, lawyers, or the police rather than to psychiatrists. Although the prevalence is low, delusional disorder is not rare. Age at onset is usually middle or late adulthood, and the course is variable. Familial transmission is suspected, and comorbidity (frequently mood disorders) may exist. Successful management is difficult and may include hospitalization, pharmacotherapy, and certain forms of psychotherapy.

Pathogenesis of delusions.

This overview of attempts to shed light on the pathogenesis of delusions provides a sense of promise, because we are grappling with the right problems, and reasons for both optimism and skepticism. Optimism is justified because some of the approaches have yielded empirical support and can be tested profitably in research. Skepticism is warranted because we remain unclear about precisely what delusions are; and we have as yet no means of identifying them with a laboratory test. Hence, we must rely on the problematic nature of clinical observation of the inner experiences of patients to make progress. The different mechanisms proposed still require considerable testing, but scrutiny of current results suggests that anomalous experience as a stimulus for delusion formation has been better documented than proposals invoking disordered reasoning or motivational deviances. Nevertheless, no view is as yet established, and each may have some relevance to solving the delusion puzzle.

Frontal brain volume and context effects in short-term recall in schizophrenia.

In a group of schizophrenic patients, magnetic resonance imaging (MRI) measures of relative frontal brain volume (total frontal volume/total cerebral volume) correlated highly with the capacity to use context as an aid to recall in a verbal memory task. The dorsolateral area of the prefrontal cortex appears to have contributed most to this effect. Recall of simple word lists without contextual features revealed no correlation with relative frontal volume. With increasing contextual organization of the material, correlations between frontal volume and recall scores increased significantly. These findings are consistent with the general proposition that impairment in the use of informational redundancy is a significant component of schizophrenic pathology.

Clozapine in the back wards.

Most reports of clozapine in treatment-refractory patients have dealt with outpatient and/or relatively less chronic samples. This report focuses on clinical outcome in an institutionalized sample, notable for chronicity, poor functioning, and representing the extreme segment of the treatment-refractory population. We analyzed the data for 50 persistently hospitalized patients referred for clozapine treatment in open trials. Dimensions of outcome assessed at baseline and periodically thereafter included psychopathology, cognitive performance, extrapyramidal side effects (EPS), and patient satisfaction. Certain features of clozapine response in institutionalized patients have been underemphasized (e.g., reduced use of restraint and seclusion, greater social interaction, reduced cost for care). Ninety-four percent of this sample showed some form of improvement with clozapine. Improvement ranged from modest (e.g., less EPS) to remarkable (e.g., discharge). An adequate clozapine trial may require more than 6 months.