Hugo A. Jørgensen

Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia?

Tardive dyskinesia is a serious motor side effect of long-term treatment with neuroleptics, with an unknown pathophysiologic basis. Brain damage and aging are prominent risk-factors, and together with the persistent character of the disorder, it is likely that long-lasting neuronal changes are involved in the pathogenesis. It has been hypothesized that striatal neurodegeneration caused by excitotoxic mechanisms and oxidative stress may play an important role in the development of the disorder, and the scope of the present work is to review the evidence supporting this hypothesis. The rat model of tardive dyskinesia has been used extensively in the field, and the usefulness of this model will be discussed. Neuroleptics are able to induce oxidative stress in vitro and increase striatal glutamatergic activity in rats, which may lead to toxic effects in the striatum. Drugs that block excitotoxicity inhibit the development of persistent oral dyskinesia in the rat model, and impaired energy metabolism leads to increased frequency of oral dyskinesia. There are also signs of altered striatal histology in rats with high frequency of oral dyskinesia. Furthermore, markers of increased oxidative stress and glutamatergic neurotransmission have been found in the cerebrospinal fluid of patients with tardive dyskinesia. In conclusion, several lines of evidence implicate neurotoxic events in the development of neuroleptic induced tardive dyskinesia.

Treatment of schizophrenia with antipsychotics in Norwegian emergency wards, a cross-sectional national study

BackgroundSurveys on prescription patterns for antipsychotics in the Scandinavian public health system are scarce despite the prevalent use of these drugs. The clinical differences between antipsychotic drugs are mainly in the areas of safety and tolerability, and international guidelines for the treatment of schizophrenia offer rational strategies to minimize the burden of side effects related to antipsychotic treatment. The implementation of treatment guidelines in clinical practice have proven difficult to achieve, as reflected by major variations in the prescription patterns of antipsychotics between different comparable regions and countries. The objective of this study was to evaluate the practice of treatment of schizophrenic patients with antipsychotics at discharge from acute inpatient settings at a national level.MethodsData from 486 discharges of patients from emergency inpatient treatment of schizophrenia were collected during a three-month period in 2005; the data were collected in a large national study that covered 75% of Norwegian hospitals receiving inpatients for acute treatment. Antipsychotic treatment, demographic variables, scores from the Global Assessment of Functioning and Health of the Nation Outcome Scales and information about comorbid conditions and prior treatment were analyzed to seek predictors for nonadherence to guidelines.ResultsIn 7.6% of the discharges no antipsychotic treatment was given; of the remaining discharges, 35.6% were prescribed antipsychotic polypharmacy and 41.9% were prescribed at least one first-generation antipsychotic (FGA). The mean chlorpromazine equivalent dose was 450 (SD 347, range 25–2800). In the multivariate regression analyses, younger age, previous inpatient treatment in the previous 12 months before index hospitalization, and a comorbid diagnosis of personality disorder or mental retardation predicted antipsychotic polypharmacy, while previous inpatient treatment in the previous 12 months also predicted prescription of at least one FGA.ConclusionOur national survey of antipsychotic treatment at discharge from emergency inpatient treatment revealed antipsychotic drug regimens that are to some degree at odds with current guidelines, with increased risk of side effects. Patients with high relapse rates, comorbid conditions, and previous inpatient treatment are especially prone to be prescribed antipsychotic drug regimens not supported by international guidelines.

Effectiveness of second generation antipsychotics: a systematic review of randomized trials

BackgroundSystematic reviews based on efficacy trials are inconclusive about which second generation antipsychotic drug (SGA) should be preferred in normal clinical practice, and studies with longer duration and more pragmatic designs are called for. Effectiveness studies, also known as naturalistic, pragmatic, practical or real life studies, adhere to these principles as they aim to mimic daily clinical practice and have longer follow-up.ObjectiveTo review the head-to-head effectiveness of SGAs in the domains of global outcomes, symptoms of disease, and tolerability.MethodsSearches were made in Embase, PubMED, and the Cochrane central register of controlled trials for effectiveness studies published from 1980 to 2008, week 1. Different combinations of the keywords antipsychotic*, neuroleptic* AND open, pragmatic, practical, naturalistic, real life, effectiveness, side effect*, unwanted effect*, tolera* AND compar* AND random* were used.ResultsSixteen different reports of randomized head-to-head comparisons of SGA effectiveness were located. There were differences regarding sample sizes, inclusion criteria and follow-up periods, as well as sources of financial sponsorship. In acute-phase and first-episode patients no differences between the SGAs were disclosed regarding alleviating symptoms of disease. Olanzapine was associated with more weight gain and adverse effects on serum lipids. In the chronic phase patients olanzapine groups had longer time to discontinuation of treatment and better treatment adherence compared to other SGAs. The majority of studies found no differences between the SGAs in alleviating symptoms of psychosis in chronically ill patients. Olanzapine was associated with more metabolic adverse effects compared to the others SGAs. There were surprisingly few between-drug differences regarding side effects. First generation antipsychotics were associated with lower total mental health care costs in 2 of 3 studies on chronically ill patients, but were also associated with more extrapyramidal side effects compared to the SGAs in several studies.ConclusionIn chronically ill patients olanzapine may have an advantage over other SGAs regarding longer time to treatment discontinuation and better drug adherence, but the drug is also associated with more metabolic side effects. More effectiveness studies on first-episode psychosis are needed.

Auditory hallucinations in schizophrenia: the role of cognitive, brain structural and genetic disturbances in the left temporal lobe

In this article we review research in our laboratory on auditory hallucinations using behavioral and MRI measure. The review consists of both previously published and new data that for the first time is presented together in a cohesive way. Auditory hallucinations are among the most common symptoms in schizophrenia, affecting more than 70% of the patients. We here advance the hypothesis that auditory hallucinations are internally generated speech perceptions that are lateralized to the left temporal lobe, in the peri-Sylvian region. From this we predict that hallucinating patients should have problems identifying a simultaneously presented external speech sound, as measured through performance on the dichotic listening (DL) paradigm with consonant–vowel syllables, since this technique lateralizes the stimulus input. Across a series of behavioral experiments, we have shown that patients with schizophrenia who experience frequent auditory hallucinations fail to demonstrate an expected right ear advantage on the dichotic listening test. Absence of a right ear advantage is indicative of a functional deficit in the left peri-Sylvian region. The results also revealed that patients with ongoing auditory hallucinations were more impaired than patients with previous hallucinations, and that a higher score on the hallucination item in a standard symptom rating scale (BPRS) correlated negatively with number of correct reports for the right ear stimulus. Moreover, we have found that schizophrenia patients fail to shift attention to the left ear stimulus, when explicitly instructed to focus on the right or left ear stimulus only, thus showing a deficit in inhibition of attention and response-inhibition. The behavioral DL data are substantiated in two MR morphometry studies that revealed significant reductions in grey matter density in the left peri-Sylvian region in hallucinating patients, and patients with reduced left temporal lobe grey matter density. Hallucinating patients also failed to show a right ear advantage in the dichotic listening test. Ongoing fMRI studies are focused on the underlying synaptic and molecular mechanisms by investigating the effects of the glutamate antagonist drug memantine on auditory perception and speech lateralization, and examination of temporal cortex-specific gene expression in the left peri-Sylvian region.

Oral dyskinesias and histopathological alterations in substantia nigra after long-term haloperidol treatment of old rats.

The pathophysiologic basis of tardive dyskinesia remains unclear, but several lines of evidence suggest that persistent neuronal changes in the basal ganglia produced by oxidative stress or glutamate toxicity may play a role, especially in the elderly. In the present study we examined whether histopathological alterations in substantia nigra are related to oral dyskinesia in a rodent model of tardive dyskinesia. Haloperidol decanoate (38 mg/kg/4 weeks) was administered to young (8 weeks) and old (38 weeks) rats for a total period of 28 weeks, and the development of vacuous chewing movements (VCM) was observed. Rats with high and low levels of VCM and saline-treated controls were analyzed for histopathological alterations. Reduced nerve cell number and atrophic neurons were prominent features in the substantia nigra of old rats with high levels of VCM. Some alterations were also present in the substantia nigra of the old rats with low levels of VCM and young rats with high VCM levels, but these were significantly less affected than the high VCM rats. These results show that the development of haloperidol-induced oral dyskinesias in old rats is associated with histopathological alterations in the substantia nigra. This suggests that nigral degeneration induced by neuroleptics may contribute to the development of persistent VCM in rats and possibly irreversible tardive dyskinesia in humans.

Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30d) treatment, there was either a decrease (1 day off) or increase (3–4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated for 1 year with haloperidol and spontaneous oral dyskinesias (i.e. vacuous chewing movements, VCMs) were recorded. In these long-term treated animals we wanted to determine if there was a correlation between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.

A peptide-containing fraction in the urine of schizophrenic patients which stimulates opiate receptors and inhibits dopamine uptake.

Abstract A factor in the urine of schizophrenic patients has been investigated for its effects on uptake of monoamines in crude synaptosomal preparations and on behaviour in rats. Urine from seven schizophrenic patients was precipitated with benzoic acid and fractionated on Sephadex G 25, P 2 gels and Fractogel, and characteristic patterns of peptide and protein-associated peptide complexes were found. One factor which showed marked biological activity (factor 3b2) was further studied. This factor strongly inhibited uptake of [ 3 H]dopamine into hypothalamic and striatal synaptosomes, and slightly reduced this uptake in hippocampal synaptosomes, uptake of [ 14 C]5-hydroxytryptamine was also some-what reduced in synaptosomes from these three structures. When injected intracerebroventricularly in rats factor 3b2 produced a characteristic behavioural syndrome, including transient ‘explosive motor behaviour’, autonomic changes, long-lasting (at least 3 weeks) ‘catalepsy’, rigidity and loss of righting reflexes. Pain sensitivity was greatly reduced, and body temperature initially rose and then it was reduced for several days. Rats with unilateral 6-hydroxydopa-mine-induced lesions of the nigrostriatal dopamine pathway showed turning ipsilateral to the lesion after injections of factor 3b2. Behavioural effects (except the autonomic effects) were partly or completely blocked by pretreatment with the opiate receptor blocker naloxone, and several of the behavioural effects were also blocked by the dopamine receptor blocker haloperidol. Repeated injections of factor 3b2 resulted in the development of tolerance, as well as cross tolerance with morphine. It was concluded that schizophrenic patients excrete in the urine peptides or peptide-like factors which have strong opiate receptor stimulating effects, and which also result in dopaminergic stimulation. The possibility that this factor is of importance in the pathogenesis of schizophrenia is discussed.

Inhibition by memantine of the development of persistent oral dyskinesias induced by long‐term haloperidol treatment of rats

1 Tardive dyskinesia (TD) is a serious side‐effect of long‐term treatment with neuroleptics. To investigate if neuroleptic‐induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1‐amino‐3,5‐dimethyladamantane), was studied in a rat model of TD. 2 In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg−1 day−1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg−1 i.p. or saline i.p. In a subsequent long‐term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg−1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long‐term treatment. 3 In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidolinduced increase in the putative TD‐analogue vacuous chewing movements (VCM). 4 In the long‐term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose‐dependently increased VCM and moving during long‐term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co‐treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5 These results suggest that long‐lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.

Antinociceptive effects of (+/-)-, (+)- and (-)-nefopam in mice.

The antinociceptive activity of (±)‐, (+)‐ and (‐)‐nefopam in mice has been examined using the hot‐plate, formalin and tail‐flick tests. Nefopam was administered by the intraperitoneal, intracerebroventricular (i.c.v.) and intrathecal (i.th.) routes. Intraperitoneal injection of (±)‐nefopam (10–20 mg kg−1) had powerful analgesic effects in the hot‐plate and formalin tests. In the tail‐flick test it produced a weak, but significant elevation of the response latencies. In spinalized animals, however, the effect was abolished, indicating that nefopam prolonged the tail‐flick latencies by activation of descending pain‐modulating pathways. (±)‐Nefopam (5–20 μg) elicited analgesia in the hot‐plate test after i.c.v. or i.th. injection. These findings suggest that nefopam has both a spinal and a supraspinal site of action. (+)‐Nefopam was significantly more potent than (‐)‐nefopam after both systemic and central administration.

Effectiveness of second-generation antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone

BackgroundNo clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line second-generation antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes.MethodsPatients ≥ 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years.ResultsA total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naïve. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups.ConclusionsQuetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis.Trial RegistrationClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529