olanzapine and Atrophy

The antipsychotic drug, olanzapine, is prescribed for postpartum psychosis. Possible adverse effects on fertility of offspring are unclear. We investigated the effects of administering olanzapine via lactation on testicular development and endocrine function of prepuberal male rats. Olanzapine was administered to mothers at 2.5, 5 or 10 mg/kg. We found in male offspring increased body weight, decreased gonadosomatic index, testicular weight and epididymal weight. The volume of seminiferous tubules, seminiferous epithelium, Leydig cells, intertubule tissue and lymphatic space was reduced in rat pups exposed to olanzapine. Tubule diameter and length, seminiferous epithelium height, Leydig cell size and nuclear diameter also were reduced. Testosterone levels were reduced in the groups exposed to olanzapine, while prolactin levels were increased. We observed histopathology in testes of animals whose mothers had been treated with 2.5 mg/kg olanzapine; more severe pathology was observed in offspring whose mothers were administered higher doses. Administration of olanzapine to mothers during lactation produced testicular and endocrine pathology in prepuberal rats in a dose-dependent manner.

Topics: Animals; Atrophy; Female; Lactation; Male; Olanzapine; Organ Size; Rats; Testis; Testosterone

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I

Topics: Antipsychotic Agents; Atrophy; Biperiden; Cerebellar Ataxia; Cerebellum; Dystonia; Dystonia Musculorum Deformans; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neck; Olanzapine; Schizophrenia

Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear.. With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology.. We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed.. This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins.

Topics: Animals; Antipsychotic Agents; Astrocytes; Atrophy; Benzodiazepines; Cell Count; Cerebral Cortex; Haloperidol; Magnetic Resonance Imaging; Male; Neuroimaging; Neurons; Olanzapine; Rats

Huntington's disease (HD) is a neurodegenerative, autosomal dominant disease that manifests with a triad of symptom clusters including movement disorder, cognitive impairment and psychiatric symptoms. We present a patient with HD who, prior to developing neurological signs and symptoms, had been exposed to war trauma and had developed posttraumatic stress disorder. Fifteen years later he manifested with dysarthria, difficulties with swallowing and involuntary movement. What brought him to psychiatrist was a heteroanamnestically noticed change in personality with irritable mood, impulsivity, aggressive outbursts in behavior and delusional ideation. Therapy was stared with haloperidol, but patient developed severe extrapiramidal side effects. Subsequent treatment with olanzapine, diazepam and omega 3 fatty acids lead to mood stabilization and better impulse control with even some improvement in motoric symptoms. To our knowledge, this is the first case report on combat related PTSD as psychiatric disorder manifested prior to HD. We discuss a possible influence of psychological stress disorder on severity of psychiatric symptoms in the HD. The importance of personalized approach in both psychopharmacological and psychotherapeutical treatment of patients with HD is emphasized. If the influence of environmental stress on the psychiatric phenotype of the disease should be confirmed by clinical trials and further studies, both screening methods and interventions aimed to reduce psychological stress in carriers of Huntington gene could be considered.

Topics: Alleles; Antipsychotic Agents; Atrophy; Benzodiazepines; Cerebral Cortex; Chromosomes, Human, Pair 4; Combat Disorders; Combined Modality Therapy; Comorbidity; Diagnosis, Differential; Diazepam; Fatty Acids, Omega-3; Genetic Testing; Humans; Huntington Disease; Magnetic Resonance Imaging; Male; Medulla Oblongata; Middle Aged; Neurologic Examination; Olanzapine; Patient Care Team; Psychotherapy; Risk Factors; Social Environment; Stress Disorders, Post-Traumatic; Trinucleotide Repeats

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

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia. In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

Topics: Adolescent; Adult; Antipsychotic Agents; Atrophy; Benzodiazepines; Cerebral Cortex; Child; Cognition Disorders; Disease Progression; Haloperidol; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Neurodegenerative Diseases; Neuroprotective Agents; Neuropsychological Tests; Olanzapine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Schizotypal Personality Disorder

The authors performed a longitudinal study of the effects on thalamic volume of switching from typical to atypical antipsychotic medications.. Magnetic resonance imaging scans were acquired from 10 subjects with chronic schizophrenia taking typical antipsychotics and 20 healthy volunteers. Subjects with schizophrenia were switched to olanzapine; both groups were rescanned.. At baseline, thalamic volumes in subjects with chronic schizophrenia were 5.8% greater than those of healthy volunteers. At follow-up, there was no significant difference between groups. Additional analysis revealed a significant positive correlation between baseline thalamic volume and dosage of typical antipsychotic medication. Higher dosages at baseline were correlated with larger reductions in volume after the switch to olanzapine.. Antipsychotic medication effects may be a factor in the wide range of thalamic volume differences reported between subjects with schizophrenia and healthy volunteers.

Topics: Adult; Antipsychotic Agents; Atrophy; Benzodiazepines; Chlorpromazine; Chronic Disease; Female; Follow-Up Studies; Humans; Hypertrophy; Longitudinal Studies; Magnetic Resonance Imaging; Male; Olanzapine; Schizophrenia; Thalamus; Therapeutic Equivalency

The study of cerebral variables associated with response to neuroleptics holds interest from both theoretical and clinical points of view. To date, no studies have aimed to identify predictors of response to olanzapine based on cerebral measurements. Here, we used magnetic resonance to assess the relationship between volumes of the prefrontal (dorsolateral and orbitofrontal) and temporal (temporal lobe and hippocampus) cortical regions and ventricles and, on the other hand, the response to olanzapine in 16 schizophrenic patients. Data from 42 healthy controls were used to calculate volume residuals in the patients, defined as deviations from the expected values, given individual age and intracranial volume. Residuals thus represent the effect of illness on regional measurements. The association between clinical change and those residuals was calculated separately for the positive, negative and total scores from the Positive and Negative Syndrome Scale (PANSS). There was a significant direct association between the degree of orbitofrontal atrophy and the improvement of positive symptoms with olanzapine. No predictors were found for change in the negative dimension. A trend was found for patients with larger ventricles to show a greater global decrease in total PANSS scores. Neither age nor duration of illness explained a significant proportion of the symptom improvement. This result, together with others from the literature, supports the idea that atypical antipsychotics may offer some benefit to patients with significant regional atrophy, and this may have implications for the choice of antipsychotic in clinical practice.

Topics: Adult; Antipsychotic Agents; Atrophy; Benzodiazepines; Hippocampus; Humans; Lateral Ventricles; Magnetic Resonance Imaging; Olanzapine; Prefrontal Cortex; Schizophrenia; Temporal Lobe

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