Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine

Aims: Aberrant dopamine transmission in extrastriatal brain regions has been repeatedly illustrated among patients with schizophrenia. Differences between typical and second‐generation antipsychotics in dopamine D₂ receptor modulation within various brain areas remain a topic for debate. The aim of the present study was therefore to investigate dopamine D_2/3 receptor apparent binding potential (BP_app) and occupancy in midbrain and temporal cortex among clozapine‐, olanzapine‐ and haloperidol‐treated schizophrenia patients. Methods: Dopamine D_2/3 binding was studied on single‐photon emission computed tomography ligand [¹²³I]epidepride in 13 schizophrenia patients treated with medication (two with haloperidol, four with olanzapine and seven with clozapine), six drug‐naïve patients and seven healthy controls. Results: Statistically significant differences in midbrain dopamine D_2/3 receptor BP_app (P = 0.015) and occupancy (P = 0.016) were observed between the clozapine, olanzapine and haloperidol groups. The lowest occupancy was found in clozapine‐treated patients (5%), followed by olanzapine‐treated patients (28%), compared to haloperidol‐treated patients (40%). No significant differences were observed in the temporal poles. Occupancy changed substantially depending on the comparison group used (either drug‐naïve vs healthy controls) in the examined brain areas (P = 0.001), showing an overestimation with all antipsychotics when the healthy control group was used. Conclusion: Both typical and second‐generation antipsychotics occupy cortical dopamine D_2/3 receptors, thus mediating therapeutic efficacy. Observed differences in midbrain dopamine D_2/3 occupancy between classical antipsychotics and second‐generation antipsychotics may have clinical relevance by modulating altered nigrostriatal dopamine neurotransmission during the acute phase of schizophrenia.     

Striatal D2/3 Binding Potential Values in Drug-Na?ve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

One of best validated findings in schizophrenia research is the association between blockade of dopamine D₂ receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D_2/3 receptor binding potential (BP_p) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D_2/3 receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [¹²³I]iodobenzamide ([¹²³I]-IBZM) was used to examine striatal D_2/3 receptor BP_p. Patients were examined before and after 6 weeks of treatment with the D_2/3 receptor antagonist amisulpride. There was a significant negative correlation between striatal D_2/3 receptor BP_p at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP_p in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP_p of dopamine D_2/3 receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BP_p have a better treatment response than patients with a high BP_p. The results further suggest that functioning may decline at high levels of dopamine receptor blockade.Key words: [¹²³I]iodobenzamide, SPECT, occupancy, amisulpride, subjective well-being     

Dopamine transporter imaging in adult patients with attention-deficit/hyperactivity disorder

The aim of this study was to provide in vivo evidence for the hypothesis that dopaminergic neurotransmission is altered in adult patients with attention-deficit/hyperactivity disorder (ADHD). We used high-resolution brain-dedicated single-photon emission computed tomography and the dopamine transporter (DAT) marker [¹²³I]FP-CIT in 17 adult treatment-naïve ADHD patients and 14 age-matched controls. Magnetic resonance imaging-based region of interest analysis was performed to quantify the DAT availability (expressed as a ratio of specific to non-displaceable binding, V₃″) in the striatum. Additionally, the specific radiotracer binding was assessed in the thalamus and the midbrain/brainstem regions (reflecting also the availability of the serotonin transporter to which [¹²³I]FP-CIT binds with moderate affinity). In the striatal areas of the ADHD patients, a significantly reduced specific tracer binding was found (V₃″: 5.18 ± 0.98; controls 6.36 ± 1.34). In contrast, the specific [¹²³I]FP-CIT binding did not differ from controls in the thalamus and midbrain/brainstem areas. These data indicate a reduced dopaminergic but not serotonergic transmitter reuptake function in adult ADHD. Further studies will have to deal with the question of whether these findings have the potential to influence treatment decisions in this complex disorder.     

Extrastriatal dopamine D2/3 receptors and cortical grey matter volumes in antipsychotic-naïve schizophrenia patients before and after initial antipsychotic treatment

Objectives: Long-term dopamine D_2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D_2/3 receptor binding potentials (BP_ND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment.

Methods: Twenty-two initially antipsychotic-naïve patients underwent magnetic resonance imaging (MRI), [¹²³I]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N?=?13) or zuclopenthixol (N?=?9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT.

Results: Neither extrastriatal D_2/3 receptor BP_ND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D_2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume.

Conclusions: The present data do not support an association between extrastriatal D_2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.     

Dyskinesia and soft neurological signs in schizophrenia: a comparative study

Objective. Several neurological abnormalities can be found at a greater frequency in patients with schizophrenia, including neurological soft signs (NSS) and signs of the “pyramidal” and “extrapyramidal” systems. We aimed to explore the frequency of movement disorders in patients with antipsychotic naïve schizophrenia and to compare and contrast with antipsychotic-treated patients and healthy controls. Methods. Twenty-two antipsychotic naive schizophrenic patients, 22 antipsychotic treated patients and 22 healthy control subjects were assessed by Neurological Evaluation (NES), Abnormal Involuntary Movements (AIMS), and Positive and Negative Syndrome (PANSS) Scales. Results. The NES scores of the never-medicated schizophrenic group were significantly higher than those of normal controls but did not differ significantly from the medicated group. Dyskinesia rates in the both schizophrenic groups were higher than in healthy controls. Medicated and non-medicated schizophrenic patient scores did not differ in AIMS with regard to facial and oral movements, but medicated patients scored higher than non-medicated subjects with respect to extremity movements. Conclusion. Our data suggest that: soft neurological signs and abnormal involuntary movements in the facial region are more prevalent in patients with schizophrenia, whether they are medicated or antipsychotic naïve. On the contrary, abnormal involuntary movements in the trunk and the extremities seem to be associated with medication.     

Receptor and Transporter Imaging Studies in Schizophrenia,Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D₂ and 5-HT_IA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D₂ receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D₂ receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HT_IA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT_IA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [¹²⁴I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.     

Increase of striatal dopamine transmission in first episode drug-naive schizophrenic patients as demonstrated by [I]IBZM SPECT

Acute psychotic exacerbation in schizophrenia is associated with a “striatal hyperdopaminergic state”. The aim of this investigation was to test this hypothesis by assessing striatal dopamine D₂ receptor availability using single photon emission computed tomography (SPECT) and the specific D₂ radioligand [¹²³I]IBZM in first episode, drug-naïve, schizophrenic patients and compare it with that in healthy control subjects. Additionally, D₂ radioligand binding was correlated with the extent of psychopathology assessed by specific rating scales including Positive and Negative Syndrome Scale (PANSS). Twenty-three acutely ill, treatment-naïve, inpatients suffering from a first acute psychosis were studied. Patients were assigned to a psychopathological syndrome-type according to PANSS positive and negative subscale results. The PANSS items delusions, conceptual disorganization, and hallucinatory behaviour were chosen to assess the extent of the acute psychotic syndrome. Patients showed a significantly lower specific [¹²³I]IBZM binding compared with the control group. Positive and negative syndrome type patients differed significantly with respect to specific IBZM binding. There was a significant negative correlation between IBZM binding and the PANSS item ‘hallucinatory behaviour’ in patients with pronounced positive symptoms. The data obtained show a significant difference between acute psychotic patients, patients with predominant negative syndrome, and healthy controls, according to the concept of a “hyperdopaminergic state” in psychotic exacerbation.     

D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia

BACKGROUND: Abnormalities in the dopaminergic system are implicated in schizophrenia. [F-18]fallypride is a highly selective, high affinity PET ligand well suited for measuring D2/D3 receptor availability in the extrastriatal regions of the brain including thalamus, prefrontal, cingulate, and temporal cortex, brain regions implicated in schizophrenia with other imaging modalities. METHODS: Resting [F-18]fallypride PET studies were acquired together with anatomical MRI for accurate coregistration and image analysis on 15 drug na?ve schizophrenics (10 men, 5 women, mean age 28.5 years) and 15 matched controls (9 men, 6 women, mean age 27.4 years). Dopamine D2/D3 receptor levels were measured as binding potential (BP). The fallypride BP images of each subject were spatially normalized and subsequently smoothed for group comparison. Measures of significance between the schizophrenic and control groups were determined using statistical parametric mapping (SPM). The medial dorsal nucleus and pulvinar were also traced on coregistered MRI for detailed assessment of BP in these regions. RESULTS: The thalamus of patients with schizophrenia had lower [F-18]fallypride BP than normal controls and this was the brain area with the greatest difference (range -8.5% to -27.2%). Left medial dorsal nucleus and left pulvinar showed the greatest decreases (-21.6% and -27.2% respectively). The patients with schizophrenia also demonstrated D2/D3 BP reduction in the amygdala region, cingulate gyrus, and the temporal cortices. CONCLUSIONS: These findings suggest that drug na?ve patients with schizophrenia have significant reductions in extrastratial D2/D3 receptor availability. The reductions were most prominent in regions of the thalamus, replicating other studies both with high affinity D2/D3 ligands and consistent with FDG-PET studies, further supporting the hypothesis of thalamic abnormalities in this patient population.     

Increase in thalamic binding of [C]PE2I in patients with schizophrenia: A positron emission tomography study of dopamine transporter

Previous in vivo imaging studies reported no difference in dopamine transporter (DAT) bindings in the striatum between control subjects and patients with schizophrenia. However, as the signals of radioligands with moderate affinity were insufficient for allowing the evaluation of small amounts of DAT, DAT binding in extrastriatal regions has not been determined. Positron emission tomography scanning using [¹¹C]PE2I was performed on eight patients with schizophrenia and twelve normal control subjects. Binding potential (BP_ND) for DAT in the caudate, putamen, thalamus and substantia nigra was calculated, using the cerebellum as reference region. In patients with schizophrenia, clinical symptoms were evaluated by Positive and Negative Syndrome Scale (PANSS). BP_ND in the thalamus of patients with schizophrenia was significantly higher than in control subjects (P = 0.044). In patients with schizophrenia, there were significantly positive correlations between BP_ND in the thalamus and total (r = 0.75), positive (r = 0.78) and negative PANSS scores (r = 0.82). Altered DAT in the thalamus might be related to the pathophysiology and clinical symptoms of schizophrenia.     

Extrastriatal dopamine D 2/3 receptor density and distribution in drug-naive schizophrenic patients

Several lines of studies have suggested the importance of cortical dopamine (DA) transmission in the pathophysiology of schizophrenia. The putative alteration of striatal D(2) receptor density in schizophrenia has been studied intensely, although extrastriatal DA activity may be more relevant for behavioral symptoms. The aim of this study was to explore extrastriatal D(2/3) density in drug-naive schizophrenic patients. We studied the extrastriatal D(2/3) receptor binding with a novel high-affinity single-photon emission tomography ligand epidepride in seven drug-naive schizophrenic patients and seven matched controls. The symptoms were rated with Positive and Negative Syndrome Scale for Schizophrenia. The findings indicated an extremely low D(2/3) receptor binding among patients in temporal cortex in both hemispheres when compared with controls (effect size 2.0-2.3), and the D(2/3) levels had negative correlations with general psychopathological (r from -0.86 to -0.90) and negative (r from -0.37 to -0.55) schizophrenic symptoms. These results support the previous hypothesis on dysfunction of mesocortical DA function behind the cognitive and negative symptoms in schizophrenia.     

Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain

The D₄ dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D₄ DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D₄ mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. ³²P-labelled RNA probes to the D₄ DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D₄ mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P<0.011) of D₄ mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D₄ receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia.     

Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP)

Objectives

Based on the hypothesis of NMDA receptor hypofunction in schizophrenia, plasma glycine, l-serine, and d-serine levels have been studied, since they could serve as biological markers. However, changes over time in the levels of these amino acids in schizophrenic patients have not been investigated. To clarify the mean plasma glycine, l-serine, and d-serine levels in patients with schizophrenia, levels of these amino acids were compared between healthy controls and patients with schizophrenia. The plasma levels of these amino acids during the clinical course of schizophrenia were also compared.

Methods

Eighty-nine Japanese patients with schizophrenia and 50 age- and gender-matched healthy controls were studied. Plasma glycine, l-serine, and d-serine levels and their ratios were measured twice, during the acute stage and during the remission stage, using high-performance liquid chromatography.

Results

The admission plasma glycine, l-serine, and d-serine levels of schizophrenic patients were higher than those of healthy controls. There were no significant differences between drug-naïve patients and healthy controls in the admission levels of the plasma amino acids, but chronically medicated patients had higher admission plasma glycine and d-serine levels. Only the d-serine level and the d-/l-serine ratio were markedly significantly increased in schizophrenic patients from the time of admission to the time of discharge as their clinical symptoms improved. In addition, the increase in the plasma d-serine levels of drug-naïve patients was correlated with improvements in positive symptoms.

Conclusions

Plasma amino acid levels, especially d-serine levels, could be useful as a “therapeutic” or “clinical state” marker in patients with acute schizophrenia.     

Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender.

BACKGROUND: The aim of the study was to examine extrastriatal dopamine D(2/3) receptor binding and psychopathology in schizophrenic patients, and to relate binding potential (BP) values to psychopathology. METHODS: Twenty-five drug-naive schizophrenic patients and 20 healthy controls were examined with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values and positive symptoms in male schizophrenic patients. They are in agreement with the hypothesis that frontal D(2/3) receptor activity is significant for positive psychotic symptoms. Additionally, the data support a thalamic hemispheric imbalance in schizophrenia.     

Phospholipase A2 activity in first episode schizophrenia: Associations with symptom severity and outcome at week 12

Abstract

Objectives. Intracellular phospholipases A₂ (inPLA₂) are activated during monoaminergic neurotranismision and act as key enzymes in cell membrane repair and remodelling, neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes and neuroinflammation. Several independent studies found increased inPLA₂ activity in drug-naïve first episode and chronic schizophrenia. This study investigates if inPLA₂ activity is associated with symptoms severity and treatment response in first episode schizophrenia (FES). Methods. InPLA₂ activity was measured in serum of 35 young FES patients (mean age: 19.36 ± 3.32, mean duration of illness: 7.53 ± 6.28 months, 16 neuroleptic-naïve) before and after 12 weeks of treatment with second-generation antipsychotic medications (olanzapine, quetiapine or risperidone), as well as in 22 healthy controls matched for age. Psychopathology and social functioning were assessed at the same time points. Results. Baseline inPLA₂ activity was significantly increased in drug-naïve and treated FES patients compared to healthy controls. Baseline inPLA₂ activity was also associated with severity of negative symptoms and lower functioning at baseline. Furthermore, baseline inPLA₂ activity was associated with improvement in negative symptoms and functioning within the first 12 weeks of treatment. Conclusions. Intracellular PLA₂ activity is increased in first episode schizophrenia and associated with symptom severity and outcome after 12 weeks of treatment. Future studies should investigate the implications of inPLA₂ activity as a potential predictor of treatment response for different antipsychotic agents.     

Dual-isotope SPECT imaging of striatal dopamine: a comparative study between never-treated and haloperidol-treated first-episode schizophrenic patients

The aim of this dual-isotope SPECT imaging study was to evaluate striatal dopamine transporter (DAT) and D2 receptor availability in first-episode never-treated and haloperidol-treated schizophrenic patients and whether the availability is associated with psychopathology. Twenty-four inpatients with a first acute schizophrenic episode were enrolled in the study; 12 of these patients were treated with haloperidol for 2 weeks before dual-isotope SPECT was performed, whereas the other 12 patients underwent the SPECT evaluation directly after enrollment. Twelve healthy control persons were also recruited and evaluated with the dual-isotope SPECT protocol. Psychopathology was assessed by the Positive and Negative Syndrome Scale and other scales. D2-radioligand binding did not differ between drug-naïve patients and the control group but was significantly lower in the haloperidol-treated group. DAT availability was also significantly lower in the haloperidol patients than in the other two groups and differed significantly between drug-naïve, positive-syndrome-type patients and healthy controls. The data obtained with the new dual-isotope SPECT technique reveal a direct effect of haloperidol at the D2 and DAT receptor level.     

The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms

The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia.     

Subsensitivity of serotonin and substance P receptors involved in nociception after repeated administration of a serotonin receptor agonist

Summary In post-mortem putamen samples from 27 schizophrenics and 27 controls D₂ receptors were measured by Scatchard analysis using³H-spiperone as a ligand. Maximum number of binding sites (B_max) and apparent dissociation constant (K_D) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in B_max values and unchanged K_D values. Withdrawal of neuroleptic drugs was followed by a normalization of the K_D values within 2 weeks and a slower reduction of B_max values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher B_max values. There was no difference in³H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).     

The role of dopamine in epilepsy

The clinical benefits of dopamine agonists in the management of epilepsy can be traced back over a century, whilst the introduction of neuroleptics into psychiatry practice 40 years ago witnessed the emergence of fits as a side effect of dopamine receptor blockade. Epidemiologists noticed a reciprocal relationship between the supposed dopaminergic overactivity syndrome of schizophrenia and epilepsy, which came to be regarded as a dopamine underactivity condition. Early pharmacological studies of epilepsy employed nonselective drugs, that often did not permit dopamine's antiepileptic action to be clearly dissociated from that of other monoamines. Likewise, the biochemical search for genetic abnormalities in brain dopamine function, as predeterminants of spontaneous epilepsy, proved largely inconclusive. The discovery of multiple dopamine receptor families (D₁ and D₂), mediating opposing influences on neuronal excitability, heralded a new era of dopamine-epilepsy research. The traditional anticonvulsant action of dopamine was attributed to D₂ receptor stimulation in the forebrain, while the advent of selective D₁ agonists with proconvulsant properties revealed for the first time that dopamine could also lower the seizure threshold from the midbrain. Whilst there is no immediate prospect of developing D₂ agonists or D₁ antagonists as clinically useful antiepileptics, there is a growing awareness that seizures might be precipitated as a consequence of treating other neurological disorders with D₂ antagonists (schizophrenia) or D₁ agonists (parkinsonism). © 1996 Wiley-Liss, Inc.     

Intracellularly recorded response of rat striatal neurons in vitro to fenoldopam and SKF 38393 following lesions of midbrain dopamine cells

The effect of long-term (6–19 weeks) 6-hydroxydopamine-induced (6-OHDA) lesions of midbrain dopamine cells on dopamine D₁-like agonist-induced changes in the excitability of rat striatal neurons was investigated in vitro using tissue slices and intracellular recording techniques. Fenoldopam and (±)-SKF 38393 predominantly decreased excitability in control preparations including striatal neurons located contralateral to 6-OHDA injection sites and neurons obtained from rats receiving sham injections or no treatment. Fenoldopam also inhibited neurons ipsilateral to lesions of midbrain dopamine cells. (±)-SKF 33393, unlike fenoldopam, produced predominantly increases in the excitability of ipsilateral striatal neurons. Superfusion of the D₁ receptor antagonist, SCH 23390, blocked fenoldopam-induced decreases in excitability but not the (±)-SKF 38393-induced excitation of neurons ipsilateral to the lesion. Sequential application of fenoldopam and quinpirole, a D₂/D₃ receptor agonist, produced responses to both drugs in a majority of neurons. The results demonstrate that inhibitory responses to fenoldopam are mediated by D₁ receptors, while excitatory effects of (±)-SKF 38393 in the striatum ipsilateral to the lesion are apparently not dependent on D₁ receptor activation. These findings also suggest that dopamine D₁ and D2/D3 receptors are able to concurrently influence the excitability of striatal neurons in the dopamine deafferentated striatum. Similar regulation of striatal neurons in vivo may contribute to dopaminergic regulation of basal ganglia output and the ability of dopaminomimetic agents to ameliorate symptoms of dopaminergic deficiency in Parkinson's disease. © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Favourable results in treatment-resistant schizophrenic patients under combination of aripiprazole with clozapine

Clozapine is still the gold standard in treatment-resistant schizophrenia. However, a substantial amount of patients do not fully recover on clozapine monotherapy. Though there is still a lack of randomised controlled studies of combination strategies in treatment-resistant schizophrenia, they are widely used. Aripiprazole is a relatively new therapeutic option due to its partial D2 agonism. Both clozapine and aripiprazole, though having a generally favourable side-effect profile, may lead to insufficient response and might provoke side effects in monotherapy. We report the case of four patients in whom we observed a distinct clinical improvement with respect to positive and negative symptoms without major side effects under a combination of clozapine and aripiprazole. The combination of clozapine action and aripiprazole-mediated D₂ receptor regulation could be responsible for the described favourable effects and for the increase of D₂ receptor blockade after adding aripiprazole to clozapine observed in one patient. A combination of clozapine and aripiprazole may be an effective therapeutic strategy for some schizophrenic patients, leading to a good response with respect to positive and negative symptoms without the occurrence of major side effects.