Psychotropic drug-induced hyponatremia: results from a drug surveillance program-an update.

Hyponatremia (HN) is the most common electrolyte imbalance (defined as a serum sodium concentration Na(S) of  < 130 mmol/l) and often induced by drugs including psychotropic drugs. AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicenter drug surveillance program that assesses severe or unusual adverse drug reactions (ADRs) occurring during treatment with psychotropic drugs. This study presents data from 462,661 psychiatric inpatients treated in participating hospitals between 1993 and 2016 and serves as an update of a previous contribution by Letmaier et al. (JAMA 15(6):739-748, 2012). A total of 210 cases of HN were observed affecting 0.05% of patients. 57.1% of cases presented symptomatically; 19.0% presented with severe symptoms (e.g., seizures, vomiting). HN occurred after a median of 7 days following the first dose or dose increase. Incidence of HN was highest among the two antiepileptic drugs oxcarbazepine (1.661% of patients treated) and carbamazepine (0.169%), followed by selective serotonin-norepinephrine reuptake inhibitors (SSNRIs, 0.088%) and selective serotonin reuptake inhibitors (0.071%). Antipsychotic drugs, tricyclic antidepressants, and mirtazapine exhibited a significantly lower incidence of HN. The risk of HN was 16-42 times higher among patients concomitantly treated with other potentially HN-inducing drugs such as diuretic drugs, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and proton pump inhibitors. Female SSNRI-users aged  ≥ 65 years concomitantly using other HN-inducing drugs were the population subgroup with the highest risk of developing HN. The identification of high-risk drug combinations and vulnerable patient subgroups represents a significant step in the improvement of drug safety and facilitates the implementation of precautionary measures.

Extrapyramidal reactions following treatment with antidepressants: Results of the AMSP multinational drug surveillance programme.

Objectives: Extrapyramidal symptoms (EPS) are a common adverse effect of antipsychotics. However, there are case reports describing EPS following treatment with antidepressants. It is not fully understood how antidepressants cause EPS, but a serotonergic input to dopaminergic pathways is a probable mechanism of action.Methods: Data from a multicenter drug-surveillance programme (AMSP, 'drug safety in psychiatry') which systemically documents severe drug reactions during psychiatric inpatient admissions, were reviewed to assess for EPS associated with antidepressant treatment. We identified 15 such cases, which were studied to detect similarities and to characterise risk factors.Results: We report on 15 patients with EPS following antidepressant-therapy between 1994 and 2016. EPS frequently occurred with selective serotonin reuptake inhibitor (SSRI) treatment alone (7/15 cases) or concomitant SSRI treatment (6/15 cases). EPS were most frequent with escitalopram-treatment (5 cases). The most common EPS was atypical dyskinesia (6/15 cases) followed by akathisia (4/15 cases). The mean age of onset for EPS was 54.93 years (SD 17.9). EPS occurred at any dosage and equally often in men and women.Conclusions: Our results highlight the possibility of EPS as an important, although uncommon, adverse effect of antidepressants. Clinicians should beware of this adverse effect and monitor early warning signs carefully.

Venous thromboembolism during treatment with antipsychotics: Results of a drug surveillance programme.

OBJECTIVES: Venous thromboembolism (VTE) can be a life-threatening medical condition that may lead to leg swelling, respiratory distress and death. METHODS: The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a continuous multicentre drug surveillance programme that assesses severe adverse drug reactions during treatment of psychiatric inpatients. We report on a total of 264,422 inpatients who were treated with antipsychotics (APs) and monitored from 1993 to 2011 in 99 psychiatric hospitals. RESULTS: During this period VTE events were reported for 89 inpatients, corresponding to an occurrence rate of 34 cases per 100,000 inpatient admissions treated with APs or 43 cases per 10,000 person-years. The occurrence of VTE was greatest in patients over the age of 65 years of age with mood disorders. The chemical class of butyrophenones (48/100,000) followed by atypical APs (36/100,000) showed the highest occurrence rate for VTE compared to thioxanthenes (23/100,000), which were less associated with VTE. If imputed alone, pipamperone (61/100,000) and risperidone (55/100,000) were most frequently associated with VTE. In general, there was no difference in occurrence rate of VTE between high- and low-potency APs. CONCLUSIONS: These results suggest that clinicians should consider AP drug exposure as a potential risk factor for VTE for patients older than 65 years. Additionally, the diagnosis of an affective disorder seems to increase the risk for VTE.

Pharmacotherapy of anxiety disorders in German-speaking countries: current status and changes between 1994 and 2011.

Over the past years, international treatment guidelines have been established for the treatment of anxiety disorders. Nevertheless, little is known as to whether the actual inpatient treatment follows these guidelines. The main goal of this study was to answer the question whether patients with anxiety disorder are treated according to treatment guidelines. A total of 2,573 psychiatric inpatients with the diagnosis of anxiety disorder (920 men, 1,653 women) were identified on the basis of the data of the international drug safety programme in psychiatry AMSP. Of these patients, 25.3% presented with phobia, 26.6% with panic disorder, 18.7% with generalized anxiety disorder (GAD), and 29.4% with other diagnoses of anxiety. In all of the patients, 12.7% did not receive any psychotropic medication and 22.9% were not treated with antidepressants. Only 59.3% of patients with GAD, 73.9% of patients with panic disorder, and 52.1% of patients with phobia were treated according to diagnostic guidelines. The majority (60.3%) of all patients received one or two psychotropic drugs, and only 3.7% received five or more psychotropic drugs. In two groups of patients (one group with phobia and one with panic disorder), the annual prescription rate of antidepressants significantly increased over time. The prescription rate for anticonvulsants in patients with GAD increased from 0% in 1997 to 41.7% in 2011, and for antipsychotics, from 40.7% in 1997 to 47.2% in 2011. In particular, patients with GAD were commonly treated with antipsychotics.

Brain electrical source imaging in manic and depressive episodes of bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) electroencephalographic (EEG) studies have reported varying results. The present study compared EEG in BD during manic and depressive episodes, using brain electrical source imaging [standardized low-resolution electromagnetic tomography (sLORETA)] to assess the cortical spatial distribution of the sources of EEG oscillation frequencies. METHODS: Two independent datasets (a total of 95 patients with bipolar I disorder, of whom 59 were female) were analyzed. Dataset #1 comprised 14 patients in a manic as well as a depressive episode. Dataset #2 comprised 26 patients in a manic episode and 55 patients in a depressive episode. From the head surface-recorded EEG, sLORETA cortical activity was computed in eight EEG frequency bands, and compared between mood states in both datasets. The results from the two datasets were combined using conjunction analysis. RESULTS: Conjunction analysis yielded significant differences between mood states: In manic compared to depressive states, patients had lesser theta frequency band activity (right-hemispheric lateral lower prefrontal and anterior temporal, mainly Brodmann areas 13, 38, and 47), and greater beta-2 and beta-3 frequency band activity (extended bilateral prefrontal-to-parietal, mainly Brodmann area 6, and the cingulate). CONCLUSIONS: The spatial organization of the brain's electrical oscillations differed in patients with BD between manic and depressive mood states. The brain areas implementing the main functions that show opposing abnormalities during manic and depressive episodes were affected by unduly increased or decreased activity (beta or theta). The discussion considers that facilitating (beta) or inhibiting (theta) electrical activity can in either case result in behavioral facilitation or inhibition, depending on the function of the brain area.

Severe psychotic exacerbation during combined treatment with aripiprazole/haloperidol after prior treatment with risperidone.

OBJECTIVE: Aripiprazole is a new generation antipsychotic drug that shows a partial agonistic activity at D(2) and 5-HT(1A) receptors. This might lead in some cases to an exacerbation of psychotic symptoms due to dopamine agonism. METHODS: We report the case of a 39-year-old woman with an ICD-10 defined schizoaffective disorder. RESULTS: Risperidone was started to treat psychotic symptoms. Psychotic symptoms disappeared but because of galactorrhoea risperidone needed to be discontinued. Subsequently, an antipsychotic treatment regimen with aripiprazole and haloperidol was prescribed. After initiating aripiprazole and haloperidol the patient's psychotic symptoms increased drastically. Therefore aripiprazole and haloperidol were discontinued. Olanzapine was prescribed and psychotic symptoms declined again. CONCLUSION: Concurrent causes for this serious adverse event may be the partial agonistic activity of aripiprazole at D(2) receptors as well as an up-regulation of dopamine receptors during prior treatment with risperidone. Both aspects may have contributed to the severe psychotic exacerbation. Clinicians should be aware of this possible, serious adverse event while switching to aripiprazole or prescribing aripiprazole with other antipsychotics. Because of their lower D(2) receptor affinity quetiapine and clozapine might be a better choice for combined treatment with aripiprazole.

Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme.

Hyponatraemia (HN) can be a life-threatening medical condition which may lead to severe neurological and psychiatric symptoms. The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicentre drug surveillance programme that assesses severe or new adverse drug reactions during psychopharmacological treatment in psychiatric inpatients. We report on a total of 263 864 psychiatric inpatients monitored from 1993 to 2007 in 80 psychiatric hospitals in Germany, Switzerland and Austria. During this period plasma sodium levels below 130 mmol/l (severe HN according to AMSP) were reported in 93 patients (relative frequency 0.04%). On average, the plasma sodium levels of all cases were 119.7 mmol/l (±5.8 s.d.); median 121 mmol/l (range 104-129 mmol/l). Patients who showed no clinical signs (n=65, 70%) had a mean sodium level of 121.3 mmol/l (±5.0 s.d.); median 122 mmol/l (range 114-129 mmol/l). By contrast, patients with clinical symptoms (n=28, 30%) had a mean sodium level of 116.0 mmol/l (±6.0 s.d.); median 117 mmol/l (range 104-125 mmol/l). HN was mainly observed during treatment with selective serotonin reuptake inhibitors (SSRIs) (0.06%), Serotonin noradrenaline reuptake inhibitors (SNRIs) (0.08%), carbamazepine (0.10%) and oxcarbazepine (1.29%); the highest rate was found for oxcarbazepine. Antipsychotics, mirtazapine and tricyclic antidepressants were only rarely involved in HN (0.003-0.005%). Combinations of several drugs known to induce HN significantly increased the risk of HN, e.g. more than 10-fold for SSRI+diuretics+ACE inhibitors (0.37%) vs. SSRI given alone (0.02%). This is clinically relevant because such combinations, e.g. SSRI+diuretics may occur especially in elderly patients, who are in general at higher risk of developing HN.

Impaired ideomotor limb apraxia in cortical and subcortical dementia: a comparison of Alzheimer's and Huntington's disease.

BACKGROUND: Although ideomotor limb apraxia is often considered to occur only in dementia with cortical involvement like Alzheimer's disease (AD), it is also frequently seen in dementia with subcortical degeneration like Huntington's disease (HD). METHODS: To assess the occurrence of ideomotor limb apraxia, 46 patients with HD (27 men) and 37 patients with AD (16 men), matched for cognitive performance, were assessed with an apraxia test battery containing tests of the imitation of meaningless hand and finger gestures, the performance of meaningful gestures and of pantomimic movements. RESULTS: There was a high frequency of ideomotor limb apraxia in both AD and HD patients. For the assessment of hands' imitation 13.5% of the AD patients and 41.3% of the HD patients were apraxic, for fingers' imitation 21.6% (AD) and 41.3% (HD) were apraxic, for gestures 27.0% (AD) and 32.6% (HD), and for the assessment of pantomimic movements 24.3% (AD) and 52.2% (HD) showed apraxia. In the AD patients, disease severity was related to the occurrence of apraxia. CONCLUSIONS: Ideomotor limb apraxia is a common sign in both groups of patients, occurring in a high percentage. For particular neuropsychological deficits, including ideomotor limb apraxia, a division of dementia in a subcortical and cortical subtype seems to be clinically not meaningful.

EEG low-resolution brain electromagnetic tomography (LORETA) in Huntington's disease.

Previous studies have shown abnormal electroencephalography (EEG) in Huntington's disease (HD). The aim of the present investigation was to compare quantitatively analyzed EEGs of HD patients and controls by means of low-resolution brain electromagnetic tomography (LORETA). Further aims were to delineate the sensitivity and utility of EEG LORETA in the progression of HD, and to correlate parameters of cognitive and motor impairment with neurophysiological variables. In 55 HD patients and 55 controls a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Power spectra and intracortical tomography were computed by LORETA in seven frequency bands and compared between groups. Spearman rank correlations were based on V-EEG and psychometric data. Statistical overall analysis by means of the omnibus significance test demonstrated significant (p < 0.01) differences between HD patients and controls. LORETA theta, alpha and beta power were decreased from early to late stages of the disease. Only advanced disease stages showed a significant increase in delta power, mainly in the right orbitofrontal cortex. Correlation analyses revealed that a decrease of alpha and theta power correlated significantly with increasing cognitive and motor decline. LORETA proved to be a sensitive instrument for detecting progressive electrophysiological changes in HD. Reduced alpha power seems to be a trait marker of HD, whereas increased prefrontal delta power seems to reflect worsening of the disease. Motor function and cognitive function deteriorate together with a decrease in alpha and theta power. This data set, so far the largest in HD research, helps to elucidate remaining uncertainties about electrophysiological abnormalities in HD.

Comparative EEG mapping studies in Huntington's disease patients and controls.

Huntington's disease (HD) is a devastating neurodegenerative disorder with prominent motor and cognitive decline. Previous studies with small sample sizes and methodological limitations have described abnormal electroencephalograms (EEG) in this cohort. The aim of the present study was to investigate objectively and quantitatively the neurophysiological basis of the disease in HD patients as compared to normal controls, utilizing EEG mapping. In 55 HD patients and 55 healthy controls, a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Evaluation of 36 EEG variables was carried out by spectral analysis and visualized by EEG mapping techniques. To elucidate drug interference, the analysis was performed for the total group, unmedicated patients only and between treated and untreated patients. Statistical overall analysis by the omnibus significance test demonstrated significant (p < 0.01 and p < 0.05) EEG differences between HD patients and controls. Subsequent univariate analysis revealed a general decrease in total power and absolute alpha and beta power, an increase in delta/theta power, and a slowing of the centroids of delta/theta, beta and total power. The slowing of the EEG in HD reflects a disturbed brain function in the sense of a vigilance decrement, electrophysiologically characterized by inhibited cortical areas (increased delta/theta power) and a lack of normal routine and excitatory activity (decreased alpha and beta power). The results are similar to those found in other dementing disorders. Medication did not affect the overall interpretation of the quantitative EEG analysis, but certain differences might be due to drug interaction, predominantly with antipsychotics. Spearman rank correlations revealed significant correlations between EEG mapping and cognitive and motor impairment in HD patients.

Family and social influences on offending in men with schizophrenia.

OBJECTIVE: Environmental influences have been reported to play a role in the genesis of both schizophrenia and violent behaviour. METHOD: We studied the central features of the family and social influences of 103 healthy non-offenders, 103 non-schizophrenic offenders, 103 schizophrenic non-offenders, and 103 schizophrenic offenders, using a semistructured instrument. RESULTS: Lower social class of origin, offending behaviour in the parental generation, loss of the father, a new partnership of the remaining parent, growing up in blended families, larger sibships and stays in foster homes during childhood and adolescence, promoted the development of offending behaviour in general. Schizophrenic patients were more likely to have relatives with schizophrenia, a finding which was more marked among offenders than non-offenders. CONCLUSIONS: We were able to identify characteristic unfavourable family and social influences which were associated in schizophrenic patients with a high risk of offending behaviour. This offers the prospect of early detection of those with schizophrenia who will go on to offend.

Typical neuroleptics vs. atypical antipsychotics in the treatment of acute mania in a natural setting.

The present retrospective chart review documents the treatment practice of in-patients suffering from acute manic or hypomanic episodes, at the Department of General Psychiatry, Medical University of Vienna between 1997 and 2001. The aim of the study was to compare the efficacy of typical neuroleptics and atypical antipsychotics as add-on therapy to mood stabilizers. A total of 119 episodes of consecutively admitted patients with ICD-10-defined acute mania (n=106) or hypomania (n=13) were included in a retrospective analysis. Two subgroups were separated out of the whole patient sample according to the medication used: (a) mood stabilizer+typical neuroleptic (n=27) and (b) mood stabilizer+atypical antipsychotic (n=39). The treatment patterns of both subgroups during the first 14 d of in-patient treatment were evaluated. The therapeutic effect was measured by the Clinical Global Impression Scale (CGI). Both patient groups showed no differences on CGI at admission. Patients treated with atypical antipsychotics showed a significantly greater clinical improvement after 14 d (p<0.005) and on discharge (p<0.05) than patients treated with typical neuroleptics. Furthermore, patients treated with atypical antipsychotics developed significantly less extrapyramidal side-effects (p<0.01) and were significantly treated less often with benzodiazepines (p<0.05) during the first 14 d compared to the group receiving typical neuroleptics. Based on our evaluation and the data available in the literature atypical antipsychotics can be considered as first choice for the treatment of acute mania as add-on therapy to mood stabilizers because of their better efficacy and side-effect profile compared to typical neuroleptics.

[Transcranial magnetic stimulation (TMS)--from diagnostic procedure to therapy]. / Transkranielle Magnetstimulation (TMS)--vom diagnostischen Verfahren zur Therapie.

Transcranial magnetic stimulation (TMS) has been a well-established diagnostic tool in neurological practice for many years. It has been shown to be a safe and well tolerated method. Lately this technique has also found its way to psychiatry for the treatment of mood disorders. Several studies which investigated TMS of deeper brain regions found antidepressive effects in analogy to electro convulsive therapy (ECT). This could present a significant advantage, because TMS provides non-invasive and painless stimulation of the cerebral cortex. The method is based on the principle that a time-varying magnetic field induces an electric field which leads to activation of inhibitory and excitatory neurons in neural tissue. The magnetic field pervades the intact scalp and skull without loss of energy. Both case reports as well as clinical studies have shown that TMS could present a promising option in the treatment of depression. A review of the literature demonstrates that further studies are needed to clarify many questions regarding technical and clinical aspects, such as dosage, duration of application, localization of the coils, as well as the impact of rapid-rate TMS and stronger magnetic field generators, before TMS will become an established tool in the treatment of psychiatric disorders.

Atypical antipsychotics in mood disorders.

Bipolar disorder is ranked as the sixth most important worldwide cause of disability. Current treatment is based chiefly on lithium and/or anticonvulsants, of which sodium valproate is the most widely used. A significant minority of patients fail to respond fully to current treatments, particularly those with mixed mania and/or rapid cycling. Many patients are unable to tolerate the side-effects of current therapy in the long term, and adverse effects may contribute to the high rate of noncompliance observed in bipolar disorder. The shortcomings of current treatments are reflected in poor outcomes: two-thirds of patients with bipolar disorder require hospitalization on more than one occasion; employment and social functioning are significantly lower than in control groups; 93% of carers suffer at least moderate distress; and 25-50% of patients are believed to attempt suicide at least once. Bipolar disorder shares some features with schizophrenia, and several atypical antipsychotics have demonstrated efficacy in bipolar disorder. Quetiapine has a particularly favourable tolerability profile, with placebo-level extrapyramidal symptoms and prolactin levels across the entire dose range combined with a neutral effect on weight during long-term use, and may be a valuable treatment option in acute mania and bipolar disorder.