Neuroleptic Exposure Research Articles

A man with an arched back

A 19-year-old Chinese man presented with a four-month history of progressive lower back pain and stiffness. He had progressive truncal arching, but no limb, cranial or vocal abnormalities. This affected his ability to walk and fall asleep. His symptoms worsened with anxiety, but improved during deep sleep. Four years prior, he had been diagnosed with depression. He was taking fluoxetine intermittently, but there was no prior neuroleptic exposure. A trial of levodopa/benserazide up to 100 mg twice daily for over three months had no effect. His brother was unaffected, but his father reported feeling a cramping sensation in his dominant hand when writing under stressful conditions – the latter had a bilateral postural hand tremor without overt dystonia on examination.

Huntington disease-like phenotype in a patient with ANO3 mutation

A 71-year-old previously well white British female developed progressive involuntary tongue movements over one year, resulting in eating difficulty and 10 kg weight loss. She had also noted involuntary perioral, facial and distal limb movements beginning 18 months earlier. These had progressively worsened. In the 3 years prior to presentation, she reported subjective memory decline, word finding difficulty and depressed mood, which improved with mirtazapine 30 mg once daily. She had no history of neuroleptic exposure.

Fluvoxamine-induced neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is an uncommon but life-threatening idiosyncratic drug reaction that occurs following neuroleptic drug exposure. The estimated incidence of NMS is though very low, resulting mortality rates range between 4% and 30%. There is increasing evidence that “Atypical” antipsychotics are associated with NMS that has a different character. NMS occurring with selective serotonin reuptake inhibitors' use is extremely rare, and it should be differentiated from serotonin syndrome. Here, we report a rare case of NMS induced by fluvoxamine.

Substantia Nigra Echogenicity Predicts Response to Drug Withdrawal in Suspected Drug-Induced Parkinsonism.

Response to drug withdrawal in patients with suspected drug-induced parkinsonism (DIP) is of prognostic and therapeutic importance, but cannot be predicted solely on clinical information. The aim of this study was to validate SN hyperechogenicity (SN+) assessed by transcranial sonography as a predictor of response to drug withdrawal in this group of patients. Patients were diagnosed according to previously published criteria and prospectively included in the study. All patients were followed until complete recovery of parkinsonian symptoms or at least for 6 months after discontinuation of the offending drug and then diagnosed as DIP or parkinsonism following neuroleptic exposure (PFNE). Transcranial sonography (TCS) findings were compared with the clinical diagnosis. Sixty patients comprised the group for the final analysis. Sixteen patients were classified as PFNE and 44 as DIP. The area of SN echogenicity was significantly increased in the PFNE group (0.23 cm2; standard deviation [SD]: 0.04), compared to the DIP group (0.14 cm2; SD, 0.05; one-way analysis of variance; P < 0.001). Normal SN was significantly associated with complete recovery after withdrawal of the parkinsonism-inducing drug (P < 0.0005). Accuracy of SN+ to distinguish PFNE from DIP was: sensitivity 81.2%; specificity 84.1%; positive predictive value 47.4%; and negative predictive value 96.2%. We believe that SN+ assessed with TCS is a valid prognostic marker in the setting of suspected DIP. It is a nonexpensive, feasible technique that can be implemented for proper counseling and guidance of treatment decisions.

Parkinson's disease without nigral degeneration: a pathological correlate of scans without evidence of dopaminergic deficit (SWEDD)?

ObjectiveTo describe 5 cases of Parkinson's disease lacking any detectable histopathology.BackgroundThe diagnosis of Parkinson's disease is supported histologically by the findings of α-synuclein immunopositive Lewy bodies and neurites and severe...

A systematic examination of brain volumetric abnormalities in recent-onset schizophrenia using voxel-based, surface-based and region-of-interest-based morphometric analyses.

BackgroundBrain morphometric abnormalities in schizophrenia have been extensively reported in the literature. Whole-brain volumetric reductions are almost universally reported by most studies irrespective of the characteristics of the samples studied (e.g., chronic/recent-onset; medicated/neuroleptic-naïve etc.). However, the same cannot be said of the reported regional morphometric abnormalities in schizophrenia. While certain regional morphometric abnormalities are more frequently reported than others, there are no such abnormalities that are universally reported across studies. Variability of socio-demographic and clinical characteristics across study samples as well as technical and methodological issues related to acquisition and analyses of brain structural images may contribute to inconsistency of brain morphometric findings in schizophrenia. The objective of the present study therefore was to systematically examine brain morphometry in patients with recent-onset schizophrenia to find out if there are significant whole-brain or regional volumetric differences detectable at the appropriate significance threshold, after attempting to control for various confounding factors that could impact brain volumes.MethodsStructural magnetic resonance images of 90 subjects (schizophrenia = 45; healthy subjects = 45) were acquired using a 3 Tesla magnet. Morphometric analyses were carried out following standard analyses pipelines of three most commonly used strategies, viz., whole-brain voxel-based morphometry, whole-brain surface-based morphometry, and between-group comparisons of regional volumes generated by automated segmentation and parcellation.ResultsIn our sample of patients having recent-onset schizophrenia with limited neuroleptic exposure, there were no significant whole brain or regional brain morphometric abnormalities noted at the appropriate statistical significance thresholds with or without including age, gender and intracranial volume or total brain volume in the statistical analyses.ConclusionsIn the background of the conflicting findings in the literature, our findings indicate that brain morphometric abnormalities may not be directly related to the schizophrenia phenotype. Analysis of the reasons for the inconsistent results across studies as well as consideration of alternate sources of variability of brain morphology in schizophrenia such as epistatic and epigenetic mechanisms could perhaps advance our understanding of structural brain alterations in schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12952-015-0030-z) contains supplementary material, which is available to authorized users.

Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

Drug-induced parkinsonism is caused by an offending drug and should resolve after the causative agent has been withdrawn. However, in a number of patients, symptoms persist or may even worsen over time, suggesting the development of concomitant Parkinson's disease. The prevalence estimates of Parkinson's disease after neuroleptic exposure are unexpectedly high, suggesting a causal relationship. We critically review available literature in this regard, and some pathophysiological hypotheses that might explain such a relationship are suggested. Some patients may have an undetermined genetic susceptibility to parkinsonism. We speculate that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead over the long-term to a self-fostering, progressive process. Knowledge gaps and future perspectives are discussed.

EFNS/MDS‐ES recommendations for the diagnosis of Parkinson's disease

A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD. Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations. For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [(123) I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD. The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease.

Dendritic and spine alterations in areas 9 and 17 in schizophrenia and Huntington chorea and the role of neuroleptic exposure

Recent morphological studies in schizophrenia suggest atrophic changes in the neuropil of the prefrontal cortex. Most recently, we showed a schizophrenia-associated decrease in MAP2 in schizophrenia, which we believed is not due to neuroleptic exposure. MAP2 is a very important protein in the assembly of micro-tubule in neurons; therefore, it plays a major role in neuronal processes like dendrites, spines and synapses. Additionally, recent studies from our lab showed decreases in dendrites in area 32 and area 9. In this study we examined the dendrites and spines in area 9 and 17 to determine if neuroleptic drugs play a role. Huntington’s patients take neuroleptics similar to schizophrenics; therefore, by comparing the two groups to controls we can determine if neuroleptics play a role in the deficits reported in schizophrenia. Our results showed a significant decrease in both basal dendrites and spines for both layers III and V in area 9 in schizophrenia compared to controls. The Huntington’s brains, on the other hand, showed no significant difference compared to controls. In area 17, there was also no significant difference when comparing the three groups. The data suggest that neuroleptic drugs may not be responsible for the changes observed in schizophrenia.

Dexamethasone induced psychosis presenting with catatonic features

Catatonia is a complex condition characterized by the presence of various motor signs and symptoms. It remains a poorly understood, poorly studied, and poorly recognized syndrome. Catatonic features are seen in a range of psychiatric conditions including psychotic disorders, mood disorders, conversion disorder and dementia. Studies have also identified over 35 medical and neurological illnesses associated with catatonia including corticosteroids exposure, central nervous system (CNS) structural damage, encephalitis and other CNS infections, seizures, metabolic disturbances, phencyclidine exposure, neuroleptic exposure, lupus cerebritis, disulfuram, porphyria, and other conditions. These medical causes of catatonia account for between 20% to 30% of such cases.

Chronic deep brain stimulation in patients with tardive dystonia without a history of major psychosis

Tardive dystonia usually occurs with a delay after neuroleptic exposure in patients with major psychosis. A subgroup of patients, however, is given such medication for "mild depression" or "neurasthenia." Tardive dystonia, in general, may respond favorably to pallidal deep brain stimulation (DBS). Nevertheless, it remains unclear thus far whether or not similar beneficial outcome is achieved with pallidal DBS in different subgroups of patients with tardive dystonia. Four women (mean age 59 years at surgery) underwent stereotactic pallidal DBS in the frame of an observational study. Tardive dystonia occurred secondary to medication with fluspirilene and haloperidol, and injection of long-acting depot neuroleptics prescribed for mild depression or "nervousness." Assessment included the Burke-Fahn-Marsden (BFM) scale preoperatively and at 12 months follow-up. Extended follow-up was available at a mean of 27.3 months postoperatively (range 16-36 months). There were no surgically related complications. All 4 patients experienced sustained statistically significant benefit from pallidal DBS. Mean improvement at 12 months was 77% for the BFM motor score (range, 45-91%; P = 0.043), and 84% at the last available follow-up (range, 70-91%; P = 0.03). This was paralleled by improvement of the BFM disability score. Chronic pallidal DBS in patients with tardive dystonia without a history of major psychosis provides sustained improvement which is similar to that in other subgroups of patients with tardive dystonia. This effect is stable on extended follow-up for up to 3 years.

18F-Fallypride binding potential in patients with schizophrenia compared to healthy controls

BackgroundMolecular imaging of dopaminergic parameters has contributed to the dopamine hypothesis of schizophrenia, expanding our understanding of pathophysiology, clinical phenomenology and treatment. Our aim in this study was to compare 18F-fallypride binding potential BPND in a group of patients with schizophrenia-spectrum illness vs. controls, with a particular focus on the cortex and thalamus. MethodsWe acquired 18F-fallypride positron emission tomography images on 33 patients with schizophrenia spectrum disorder (28 with schizophrenia; 5 with schizoaffective disorder) and 18 normal controls. Twenty-four patients were absolutely neuroleptic naïve and nine were previously medicated, although only four had a lifetime neuroleptic exposure of greater than two weeks. Parametric images of 18F-fallypride BPND were calculated to compare binding across subjects. ResultsDecreased BPND was observed in the medial dorsal nucleus of the thalamus, prefrontal cortex, lateral temporal lobe and primary auditory cortex. These findings were most marked in subjects who had never previously received medication. ConclusionsThe regions with decreased BPND tend to match brain regions previously reported to show alterations in metabolic activity and blood flow and areas associated with the symptoms of schizophrenia.

Anterior cingulate and paracingulate sulci morphology in patients with schizophrenia

The anterior cingulate cortex is a cerebral region engaged in several emotional and cognitive functions. The aim of this study was to investigate possible anterior cingulate and paracingulate sulcal abnormalities in schizophrenia. Twenty-three patients with DSM-IV diagnoses of schizophrenia were compared with 23 healthy subjects matched for age, gender, and parental socioeconomic status. Magnetic resonance images were used to explore the morphology of these regions, with volume and maximum depth being measured by an automated method of sulcal recognition. Additionally, voxel-based morphometry (VBM) was performed to analyze possible reduction in gray and white matter of the anterior cingulate region. A smaller volume of the left anterior cingulate sulcus (ACS) was observed in patients with schizophrenia when compared with healthy controls. Furthermore, female patients showed a reduction in volume of the left ACS and an increase of the right paracingulate sulcus (PCS) compared to female controls. There was also a significant relationship between the depth of right PCS and neuroleptic exposure. VBM analysis showed a reduction in left anterior cingulate gray matter. These findings provide further evidence of left anterior middle frontal cortex abnormalities in schizophrenia. In addition, the results suggest gender differences in the structural abnormalities of the illness.

Drs. Nelson and Papakostas Reply

Drs. Nelson and Papakostas Reply

Frequency and Correlates of Involuntary Emotional Expression Disorder in Parkinson's Disease

Frequency and Correlates of Involuntary Emotional Expression Disorder in Parkinson's Disease

Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder

Deficits in the expression of oligodendrocyte and myelin genes have been described in numerous cortical regions in schizophrenia and affective disorders; however, relatively little attention has been paid to subcortical structures. Here we employed quantitative real time PCR to examine the mRNA expression of 17 genes that are expressed by oligodendrocyte precursors (OLPs) and their derivatives, including astrocytes. Four subcortical regions were examined (the anteroventral (AV) and mediodorsal thalamic nuclei (MDN), internal capsule (IC) and putamen (Put)) in postmortem material from subjects (age 25–68 at time of death) with no known psychiatric history (NCs) as well as in subjects with schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BPD). In all regions examined, genes expressed after the terminal differentiation of oligodendrocytes tended to have lower levels of mRNA expression in subjects with SZ compared to NCs. These differences were statistically significant across regions for four genes (CNP, GALC, MAG and MOG) and approached significance for TF. No genes were under expressed in MDD. Only TF was under expressed in BPD and only in the IC. In contrast, two astrocyte-associated genes (GFAP and ALDH1L1) had higher mean expression levels across regions in all psychiatric groups relative to NCs. These differences reached statistical significance for SZ and MDD relative to NCs. There were no age by diagnosis interactions. The majority of age regressions had negative slopes for the expression of oligodendrocyte-associated genes. GFAP but not ALDH1L1 expression was significantly and positively correlated with age in the MDN, AV and Put. Across subject groups the expression of both astrocyte genes was highly correlated with cumulative neuroleptic exposure in all regions except the Put. Significant positive correlations were also observed in some regions between cumulative neuroleptic exposure and the expression of genes associated with mature oligodendrocytes as well as with bipotential OLPs. Multiple negative correlations were observed between the mRNA expression of astrocyte genes and genes expressed by terminally differentiated oligodendrocytes. These data are discussed in the context of myelin turnover and potential effects of psychiatric illness as well as medications on the developmental fate of OLPs.

The current prevalence and factors associated with tardive dyskinesia among Filipino schizophrenic patients

ObjectiveTo determine the prevalence of and the factors associated with tardive dyskinesia (TD) among Filipino patients with schizophrenia admitted at the National Center for Mental Health. Study DesignCross-sectional study. MethodsA total of 227 inpatients fulfilling the DSM-IV TR criteria for schizophrenia participated in the study. Demographic data including age, disease duration and medication intake were obtained. The Abnormal Involuntary Movement Scale (AIMS) and Simpson Angus Rating Scale (SARS) were performed on all patients. Odds of developing TD in relation to the different variables were computed. The association between study variables and development of TD was also evaluated using the Chi-square test. FindingsOur cohort of patients had a mean age of 40 (range: 19–73years old), had a mean disease duration of 6years, had a daily neuroleptic dose of 700mg in chlorpromazine equivalent, and had a lifetime neuroleptic exposure of at least 5years. The prevalence rate of TD was 20.3% (46 out of 227 patients). Fifty-three percent of patients had significant extrapyramidal features (SARS ≥3). TD was noted more in females and older age groups. The other factors associated with TD: were those patients with longer duration of illness and those patients with longer cumulative exposure to neuroleptic drugs. There was no association found with regard to the presence of diabetes mellitus type II, to the use of anticholinergic drugs, to the history of substance abuse and to the history of electroconvulsive therapy. ConclusionsDespite the predominant use of first-generation antipsychotic agents, the prevalence of TD among Filipino schizophrenic patients is similar to that reported among Asians, but lower than that reported among our Western counterparts. The results may be affected by differences in methodological, racial and genetic determinants.

Tardive parkinsonism in a bipolar patient: Post-mortem examination supports a physiological rather than pathological dysfunction

We describe a case of tardive parkinsonism in the setting of bipolar syndrome, and we offer pathological confirmation that idiopathic Parkinson disease was not the underlying etiology. A 74-year-old Hispanic woman with a history of bipolar disease was noted to have oro-buccal-lingual chorea and parkinsonian symptoms such as resting tremor, rigidity, bradykinesia, and gait disorder persisting several months after neuroleptic discontinuation. She had minor improvement in ambulation with levodopa treatment, and she significantly improved in ambulation only during her manic states. Examination of the subject's post-mortem brain revealed no explicit evidence of degeneration in substantia nigra or other brainstem centers, and no nigral or cortical Lewy bodies were present. Glial cytoplasmic inclusions (characteristic of multiple systems atrophy) and globose neurofibrillary tangles (seen in progressive supranuclear palsy) were not seen either. This patient's presentation was most consistent with neuroleptic-induced parkinsonism and tardive dyskinesia; the etiology was likely related to previous neuroleptic exposure.

P03-134 Does the degree of smoking effect the severity of tardive dyskinesia?

Background:Tardive dyskinesia (TD) is a movement disorder observed in a chronic neuroleptic treatment. Smoking is presumed to increase the prevalence of TD. the question of a cause-effect-relationship between smoking and TD, however, remains to be answered. Purpose of this study was to examine the correlation between the degree of smoking and the severity of TD with respect to differences caused by medication.Methods:We examined 60 patients suffering from schizophrenia and TD. We compared a clozapine-treated group with a group treated with typical neuroleptics. Movement disorders were assessed using the Abnormal-Involuntary-Movement-Scale and the technical device Digital-Image-Processing providing rater independent information on perioral movements.Results:We found a strong correlation (.80&lt; r&lt; .90, always p&lt; .0001) between degree of smoking and severity of TD. Repeated measurements revealed a positive correlation between changes in cigarette consumption and changes of the severity of TD (p&lt; .0001). Analyses of covariance indicated a significant group-effect with a lower severity of TD in the clozapine-group compared to the typical-neuroleptics-group (p=.010). Interaction-analyses indicated a higher impact of smoking on the severity of TD in the typical-neuroleptics-group compared to the clozapine-group (p=.033) (Diehl et al., 2008).Conclusion:Concerning a possible cause-effect-relationship between smoking and TD, smoking is more of a general health-hazard than neuroleptic exposure in terms of TD.

Treatment of Tardive Dyskinesia by tetrabenazine, clonazepam and vitamin E

Byline: Himanshu. Sharma Sir, The term tardive dyskinesia has been used to refer to a group of delayed-onset abnormal involuntary movement disorders that present with rapid, repetitive, stereotypic choreoathetoid movements mostly involving the oral, buccal, and lingual areas or the trunk (oro-bucco-lingual variety ).[sup] [1] The word Tardiv e means late appearing movements which start after 3months of neuroleptic exposure.[sup] [2] The annual rate is estimated at 5% for the early years, the cumulative rates over 5 years being between 20-26%.[sup] [3] Most patients with TD have schizophrenia but it can develop in-patients with depression or anxiety. Risk factors for TD are age over 40 years, affective disorder, Negroes, prolonged use and use of high potency neuroleptics in high doses, early occurrence of drug-induced Parkinson's disease, and female gender and smoking, chronic use of anticholinergic drugs and diabetes mellitus.[sup] [1],[3],[4] Of the various pathogenic mechanisms proposed, dopamine receptor hypersensitivity, damage to GABA containing -neurons and free radical formation from catecholamine metabolism are the most widely accepted.[sup] [5] Following are some of the proposed guidelines for its treatment: 1) minimal dose of the causative antipsychotic or switching over to clozapine, after tapering off the offending antipsychotic drug slowly.[sup] [1] 2) Dopamine-depleting drugs -Reserpine (1 to 8 mg/day), Tetrabenazine (25 to 150 mg/day).[sup] [4],[6] 3) GABA-enhancing drugs Clonazepam (1 to 4 mg/day), Valproate, Vigabatrin, Baclofen, 4) Antioxidants: Vitamin E 800 IU/bid.[sup] [1],[7] A 34-year-old male was referred to the Psychiatry OPD of our hospital with complaints of involuntary movement of orofacial region along with difficulty in breathing and swallowing, pain in nuchal region and backache. A detailed examination revealed that the patient had complex repetitive movements of orofacial region including forehead and eyebrows raising, eye closure, puckering of lips, to and fro movements of head and neck, protrusion of and twisting and darting out movement tongue in between the parted lips and repeated clenching of teeth. The patient reported that 3 years ago he had faced some financial loss as result of which he suffered from a bout of depression for which he consulted a private psychiatrist who prescribed him Trifluoperazine 10 mg along with T.Citalopram 20mg and T. Trihexyphenidyl 2mg and T. Propranolol 10-mg tid. After 2 years the patient developed TD. Patient was nonalcoholic but chronic smoker and tobacco chewer since 15 years. His baseline assessment of abnormal involuntary movement scale (AIMS)[sup] [8] revealed a score of 21 qualifying for diagnosis of Tardive Dyskinesia (TD) . All psychotropic drugs were tapered off and a course of Tetrabenazine 25mg 1/2 hs bid was started which was increased to 25mg bid and then tid after 2 weeks. In addition to this Clonazepam 0.5 mg I hs and Cap Vit E 400 mg 1 OD were added. The patient reported a dramatic improvement within first 2 weeks of starting the treatment (AIMS score-13) and finally achieving a score of AIMS - 10 at the end of four weeks. …