clozapine and Atrophy

Studies of brain morphology in schizophrenia may be informative about basic pathophysiologic processes, provide clinically useful indicators of treatment response, and lead to the identification of markers for selective treatment effects. This paper reviews findings from magnetic resonance imaging studies of patients with schizophrenia conducted at Hillside Hospital, with special attention to (1) findings that have helped distinguish patients who respond well to typical neuroleptics from those who have gone on to trials of clozapine, (2) the capacity of morphological measures to predict clozapine treatment response, and (3) the possibility that selective hypertrophy of striatal structure may be caused by chronic treatment with typical neuroleptics, but not by clozapine.

Topics: Atrophy; Basal Ganglia; Brain; Clozapine; Corpus Striatum; Humans; Magnetic Resonance Imaging; Schizophrenia

Drug-resistant epilepsy causes great clinical danger and still lacks effective treatments.. Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance.. In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin-resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long-term low-frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off-target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug-resistant patients was related to the usage of sodium channel inhibitors.. These results highlight that the subicular pyramidal neurons may be a key switch control of drug-resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626-640.

Topics: Animals; Atrophy; Clozapine; Drug Resistant Epilepsy; Electric Stimulation; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Male; Neural Inhibition; Optogenetics; Phenytoin; Pyramidal Cells; Rats; Sodium Channel Blockers; Sodium Channels

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

Topics: Adult; Antipsychotic Agents; Atrophy; Case-Control Studies; Cerebral Cortex; Child, Preschool; Clozapine; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Statistics, Nonparametric; Young Adult

Topics: Adolescent; Amantadine; Anticonvulsants; Antiparkinson Agents; Antipsychotic Agents; Atrophy; Catatonia; Cerebral Cortex; Clozapine; Drug Therapy, Combination; Humans; Magnetic Resonance Imaging; Male; Memantine; Schizophrenia; Valproic Acid

Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition.. To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder.. This study used postmortem human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9), and unaffected control participants (n=19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed.. The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters.. The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/μm) compared with control participants (0.31 [0.05] spines/μm) (P=.02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/μm) but just missed significance when compared with control participants (P=.06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [P=.003]; individuals with bipolar disorder vs controls: 25.8% reduction [P=.005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] μm, respectively) compared with controls (301.8 [75.1] μm) (individuals with schizophrenia vs controls: 18.3% reduction [P=.005]; individuals with bipolar disorder vs controls: 18.6% reduction [P=.005]).. Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features.

Topics: Animals; Atrophy; Bipolar Disorder; Case-Control Studies; Clozapine; Dendritic Spines; Female; Frontal Lobe; Haloperidol; Humans; Male; Middle Aged; Prefrontal Cortex; Pyramidal Cells; Rats; Schizophrenia

Dyke-Davidoff-Masson syndrome, or cerebral hemiatrophy, is a pre- or perinatally acquired entity characterized by predominantly neurologic symptoms, such as seizures, facial asymmetry, contralateral hemiplegia, and mental retardation. Psychiatric symptoms are rarely reported. We report the first case of left cerebral hemiatrophy and a late onset of treatment-resistant schizoaffective disorder after a stressful life event. The patient finally responded well to clozapine. The clinical history and results from structural neuroimaging are highlighted to discuss the possible developmental bias for psychotic disorders.

Topics: Adult; Antipsychotic Agents; Atrophy; Brain; Brain Diseases; Clozapine; Facial Asymmetry; Hemiplegia; Humans; Magnetic Resonance Imaging; Male; Psychotic Disorders; Syndrome; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Atrophy; Caudate Nucleus; Clonazepam; Clozapine; Dibenzothiazepines; Electromyography; Fluoxetine; Humans; Magnetic Resonance Imaging; Male; Mouth Protectors; Neuroacanthocytosis; Obsessive-Compulsive Disorder; Quetiapine Fumarate; Self-Injurious Behavior

Recent volumetric magnetic resonance imaging (MRI) studies have suggested brain volume changes in schizophrenia to be progressive in nature. Whether this is a global process or some brain areas are more affected than others is not known. In a 5-year longitudinal study, MRI whole brain scans were obtained from 96 patients with schizophrenia and 113 matched healthy comparison subjects. Changes over time in focal gray and white matter were measured with voxel-based morphometry throughout the brain. Over the 5-year interval, excessive decreases in gray matter density were found in patients in the left superior frontal area (Brodmann areas 9/10), left superior temporal gyrus (Brodmann area 42), right caudate nucleus, and right thalamus as compared to healthy individuals. Excessive gray matter density decrease in the superior frontal gray matter was related to increased number of hospitalizations, whereas a higher cumulative dose of clozapine and olanzapine during the scan interval was related to lesser decreases in this area. In conclusion, gray matter density loss occurs across the course of the illness in schizophrenia, predominantly in left frontal and temporal cortices. Moreover, the progression in left frontal density loss appears to be related to an increased number of psychotic episodes, with atypical antipsychotic medication attenuating these changes.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Atrophy; Benzodiazepines; Brain; Caudate Nucleus; Clozapine; Disease Progression; Female; Follow-Up Studies; Frontal Lobe; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Olanzapine; Schizophrenia; Temporal Lobe; Thalamus; Time Factors

The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients were analyzed: treatment-naïve patients (n = 17) and chronic treatment-resistant patients (n = 12). Treatment-naïve patients received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups of patients presented GM increases and WM decreases in the parietal and occipital lobes (p < .005). Frontal GM also increased in the chronic group with clozapine. There was a significant (p < .001) inverse relationship between the baseline volumes (GM deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus, treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs further exploration.

Topics: Adult; Antipsychotic Agents; Atrophy; Brain; Chronic Disease; Clozapine; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Risperidone; Schizophrenia

Olanzapine is an atypical antipsychotic with a low incidence of extrapyramidal-motoric side effects. Its chemical structure is related to clozapine, which is known to induce neutropenia in up to 3% and agranulocytosis in approximately 1% of patients. It has been discussed controversially whether olanzapine also has a potential to induce neutropenia and agranulocytosis. Up to now, seven case reports of haematopoetic disturbances during olanzapine treatment have been published, including one case of olanzapine-induced agranulocytosis (Naumann et al. 1999), two cases of neutropenia (Steinwachs et al. 1999) and one leucopenia (Meissner et al. 1999). We report three subjects with reversible neutropenia under olanzapine, with rapid normalisation of neutrophil cell counts after discontinuation of olanzapine. In one case neutropenia occurred after administration of a single dose of olanzapine, in another case after 6 weeks of treatment. In both cases, patients had no clinical complications. In the third case, neutropenia appeared after 1.5 years of treatment followed by development of pneumonia. Two cases were recorded within the German drug surveillance project (AMSP); the third case was observed in a randomised, double-blind, multicentre study comparing olanzapine with clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Atrophy; Benzodiazepines; Clozapine; Female; Frontal Lobe; Humans; Neutropenia; Olanzapine; Parietal Lobe; Schizophrenia

Increased sulcal widening in the prefrontal cortex of patients with schizophrenia may be associated with a poor treatment response to clozapine. To further evaluate this, we examined data from patients treated with clozapine in our center. Patients with the greatest degree of improvement (n=26) and those with no improvement (n=10) were compared. Computerized tomography (CT) scans were rated blindly on a visual scale of prefrontal sulcal widening. Patients with the greatest degree of functional improvement had significantly less prefrontal sulcal widening than those whose symptoms remained unchanged. There was no relationship between clozapine response and general sulcal widening. These data support the link between the superior therapeutic efficacy of clozapine and the integrity of the prefrontal cortex.

Topics: Adult; Antipsychotic Agents; Atrophy; Clozapine; Cross-Sectional Studies; Humans; Middle Aged; Prefrontal Cortex; Schizophrenia; Tomography, X-Ray Computed; Treatment Failure