Dopamine and schizophrenia
(86 References)
(2002). "Schizophrenia gene discovery." Harv Ment Health Lett
18(9): 7-8.
Abi-Dargham, A., O. Mawlawi, et al. (2002). "Prefrontal dopamine D1 receptors
and working memory in schizophrenia." J Neurosci 22(9): 3708-19.
Studies in nonhuman primates documented that appropriate stimulation of dopamine
(DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for
working memory processing. The defective ability of patients with schizophrenia
at working memory tasks is a core feature of this illness. It has been
postulated that this impairment relates to a deficiency in mesocortical DA
function. In this study, D1 receptor availability was measured with positron
emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16
patients with schizophrenia (seven drug-naive and nine drug-free patients) and
16 matched healthy controls. [11C]NNC 112 binding potential (BP) was
significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/-
0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In
patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong
predictor of poor performance at the n-back task, a test of working memory.
These findings confirm that alteration of DLPFC D1 receptor transmission is
involved in working memory deficits presented by patients with schizophrenia.
Increased D1 receptor availability observed in patients with schizophrenia might
represent a compensatory (but ineffective) upregulation secondary to sustained
deficiency in mesocortical DA function.
Anney, R. J., M. I. Rees, et al. (2002). "Characterisation, mutation detection,
and association analysis of alternative promoters and 5' UTRs of the human
dopamine D3 receptor gene in schizophrenia." Mol Psychiatry 7(5):
493-502.
The dopamine D(3) receptor gene (DRD3) is a candidate for a number of
psychiatric conditions including schizophrenia, bipolar disorder and alcohol and
drug abuse. Previous studies have reported associations between polymorphisms in
DRD3 and these disorders, but these findings may have reflected linkage
disequilibrium with pathogenic variants that are further upstream. We have
isolated and sequenced approximately 9 kb of genomic sequence upstream of the
human DRD3 translational start site. Using 5' RACE, we have identified within
this region three additional exons and two putative promoter regions which show
promoter activity in three different cell lines. A 5' UTR identified only in
lymphoblasts is spread over three exons and is 353 bp long. A second 5' UTR,
found in adult and fetal brain, lymphocytes, kidney and placenta is spread over
two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to
a previously reported EST, but corresponding mRNA could not be found in the
tissues above. The EST, 5' UTRs and putative promoter regions have been analysed
for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which
were tested for association in a large sample of unrelated patients with
schizophrenia and matched controls. No associations were observed with
schizophrenia. In addition we failed to replicate previous findings of
association with homozygosity of the Ser9Gly variant. The results from this
study imply that neither the coding nor the regulatory region of DRD3 plays a
major role in predisposition to schizophrenia.
Baghdadli, A., V. Gonnier, et al. (2002). "[Review of psychopharmacological
treatments in adolescents and adults with autistic disorders]." Encephale
28(3): 248-54.
Autism is an early developmental disorder. It leads to severe and durable
disturbances. Given this problem, no treatment can be excluded a priori. Thus,
many approaches are used to deal with autistic disorders. In France,
pharmacological treatments are, for instance, largely and mostly used in adults.
In the USA, these treatments concern 50% of persons with autism of any age.
Nevertheless, they are rarely based on controlled studies. At the present,
however, prescriptions and expected effects appear to be hard to localize.
Furthermore, only few controlled studies validate their use. Aim - We offer a
review of studies about medical treatments used in adolescents and adults with
autism. They are classified in 3 categories: the first (category I) includes
drugs used for their neurochemical effects focusing on autistic signs. The
second (category II) covers drugs used for treatment of behavioural disorders
frequently associated with autism. The third (category III) corresponds to a
wide range of drugs or vitamins for wich only few case studies exist reporting
irregular positive effects. The main hypothesis of this review is that autism
involves a dysfunction of the neuromediation systems. This hypothesis opens new
perspectives in the research of medical treatments in autism by focusing on
molecules, which are supposed to have an effect on neuromediation systems.
Method - Our review is based on studies, which have been published during the
past twenty years. For many studies, data are limited to adolescents and adults.
So we expanded our review to data available in children. The data bases that we
have used are medline and psyclit. Keywords have been chosen according to:
pharmacological considerations (psychotropic, psychoactive drugs,
psychopharmacology) and clinical symptoms (autism, automutilations, aggressive
behavior, and hyperactivity). Hypothesis of a dysfunction in the neuromediation
systems in autism - Many studies exist about biochemical abnormalities in
autism. As in schizophrenia and mental retardation, dysfunctions of the
neuromediation systems are considered to be etiological factors. In 30% of
people with autism the most regular dysfunction is the increase of serotonine.
This led to the serotoninergic hypothesis in autism and to the use of active
drugs in the serotonine system. However, the presence of other neurometabolic
abnormalities also motivates the use of drugs, supposed to be active in other
neuromediation systems. Pharmacological treatments in autism - Category I
section sign 1 Active drugs in the dopamine system. Haloperidol (Dopamine
antagonist): The effects of this molecule have been broadly studied in autism.
Results indicate high efficiency in some symptoms of autism (lack in social
behaviour, stereotypical behaviour) and in behavioural impairments that may be
associated with autism (aggressive behaviour, hyperactivity). Its side effects,
particulary the risk of late dyskinesy, make atypical antipsychotics preferable
because of their lower risks. Risperidone (Dopamine and serotonine antagonist):
Among several studies only few have been controlled. They indicate that
Risperidone has positive effects on the behaviour and is quite well tolerated.
section sign 2 Active drugs in the serotonine system. Clomipramine: after
promising results, the medium-term efficiency has decreased and severe side
effects have limited its use. Fluvoxamine, Fluoxetine, Sertraline (Specific
serotonine drugs): Their efficiency has been mainly tested through open studies
and their results are contrasted. In some cases, social behaviours have improved
and aggressiveness and stereotyped behaviours have decreased. Fenfluramine: At
present, this drug is removed from the market. Yet, some studies have suggested
that it improves behavioural disturbances as well as performances in autism.
section sign 3 Active drugs in the opiate system. Naltrexone: Several controlled
studies have indicated an improvement in social and aggressive behaviours.
Nevertheless, these studies have used small size sample and have not been
replicated. Category II. This category correspond to drugs supposed to be active
on neurochemical disturbances found in autism but their target symptoms are not
autism specific signs as defined by the ICD 10. Buspirone: This serotonine
agonist may have a good impact on emotional disorders and sleeping confusions.
Methylphenidate: Most of the current studies about this noradrenergic drug
concern children. The results are variable. Paradoxical effects may exist in
children with severe mental retardation. Propanolol: Some isolated studies habe
reported its efficiency on behavioural disturbances. Clonidine: This adrenergic
drug treats efficiently some cases of aggressive behaviour and hyperactivity.
Category III. This category contains a wide range of drugs, vitamins or method
used in autism after sporadic observations of their positive effects. Secretine:
An important improvement has been reported in isolated cases. However,
controlled studies in children do not confirm these results. Vitamines B6, B12
and Magnesium: An improvement in socialization and in behavioural disorders have
been reported in some cases, but these results are not yet confirmed. Lithium,
Carbamazepine, Valproate: Results of some case studies have found it to be
efficient in cyclic disorders. Gluten and casein free diet: An improvement of
social behaviour have been reported by some parents after these diets. No
controlled study has validated this observation. Conclusion - There is no
consensus on the use of psychopharmacological treatments in autism. Although
there exist many clinical observations, only few controlled studies have
validated the efficiency and safety of these treatments. At the present time and
until having sufficient studies, drugs are generally limited to severe
disorders, for which usual psycho-educational approaches are insufficient.
Ballmaier, M., M. Zoli, et al. (2002). "Preferential alterations in the
mesolimbic dopamine pathway of heterozygous reeler mice: an emerging
animal-based model of schizophrenia." Eur J Neurosci 15(7):
1197-205.
Based on a number of neuroanatomical and behavioural similarities, recent
evidence suggests that heterozygous reeler mice, haploinsufficient for reelin
expression, represent a useful model of psychosis vulnerability. As brain
mesolimbic dopamine pathways have been proposed to be associated with the
pathophysiology of psychotic disorders, we thought it would be of interest to
examine whether these animals present disturbances in the mesolimbic dopamine
system. To this end we studied by immunocytochemical, in situ hybridization
procedures and receptor autoradiography, several markers of the
mesotelencephalic dopamine pathway in heterozygous reeler mice and controls. We
report that heterozygous reeler mice exhibit a reduction in the number of
tyrosine hydroxylase-immunoreactive cell bodies and tyrosine hydroxylase mRNA
levels in the ventral tegmental area, as well as a reduction of tyrosine
hydroxylase and dopamine transporter immunoreactivity in the dopamine terminal
fields of the limbic striatum. In these areas we also observed a reduction of
dopamine D2 receptor mRNA. Finally, a marked increase in D3 receptor mRNA levels
was observed concomitant with a significant increase in D3 binding sites. On the
contrary, the nigrostriatal pathway did not show any significant alteration in
heterozygous reeler mice with regards to the dopaminergic markers examined in
substantia nigra cell bodies and dorsal striatum dopamine terminal fields. These
results suggest a specific link between reelin-related neuronal pathology and
dopamine involvement in the pathophysiology of psychotic disorders.
Biglan, K. M. and R. G. Holloway (2002). "A review of pramipexole and its
clinical utility in Parkinson's disease." Expert Opin Pharmacother 3(2):
197-210.
Parkinson's disease (PD) is a common neurodegenerative disorder characterised by
selective loss of dopaminergic neurones in the substantia nigra and resulting in
progressive disability. Therapy has focused on replacing depleted dopamine (DA)
via supplementation with levodopa or DA agonists. Pramipexole (Mirapex((R)),
Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence
from preclinical studies and clinical trials have proven the effectiveness of
this agent in ameliorating the symptoms of PD. There is also non-human evidence
that pramipexole may be neuroprotective and could therefore possibly slow
disease progression; however, this has yet to be proven in humans. The use of
pramipexole may be limited by its side effect profile compared to standard
therapies and its relatively higher cost compared to levodopa. Despite these
concerns, pramipexole does have a role in the treatment of PD in all stages of
the illness and may arguably be the treatment of choice in early disease. In
addition to its use in PD, pramipexole has shown some utility in the treatment
of restless legs syndrome (RLS), depression and schizophrenia.
Binder, E. B., R. E. Gross, et al. (2002). "Effects of neurotensin receptor
antagonism on latent inhibition in Sprague-Dawley rats." Psychopharmacology (Berl)
161(3): 288-95.
RATIONALE: It has been postulated that the tridecapeptide neurotensin (NT)
functions as an endogenous antipsychotic peptide. A critical test of this
hypothesis would be to determine if NT is involved in the expression of latent
inhibition (LI), a psychophysiological and pharmacological model of
schizophrenia. OBJECTIVE: This report describes the effects of disrupting NT
neurotransmission by systemic administration of the NT receptor antagonists
SR48692 and SR142948A on the acquisition of LI in rats. METHODS: The effects of
30-300 microg/kg SR48692 or 0.1-100 microg/kg SR142948A on the expression of LI
following 0, 20 or 30 pre-exposures were first investigated. This was followed
by the assessment of the effects of 10 microg/kg SR142948 A on the LI effect of
increasing stimulus pre-exposures (10-40). Finally, the role of dopamine
transmission in the effects of SR142948A on the acquisition of LI (30
pre-exposures) was tested by coadministering 10 microg/kg SR142948A and 100
mg/kg of the dopamine D(2) antagonist sulpiride. RESULTS: The higher tested
doses of SR48692 (100-300 microg/kg) and SR142948A (10-100 microg/kg) decreased
acquisition of LI following 20, 30 and even 40 pre-exposures to the
to-be-conditioned stimulus. Cotreatment with the dopamine D(2) antagonist
sulpiride prevented the LI-disrupting effects of SR142948A.CONCLUSIONS: NT
neurotransmission appears to be necessary for the acquisition of LI. The main
effect of NT receptor antagonism is a disruption of LI, most likely via
enhancement of dopamine transmission. This effect is opposite that of
antipsychotic drugs, which have been shown to enhance NT release, supporting the
hypothesis of NT as an endogenous antipsychotic peptide.
Boksa, P., Y. Zhang, et al. (2002). "Dopamine d1 receptor changes due to
caesarean section birth: effects of anesthesia, developmental time course, and
functional consequences." Exp Neurol 175(2): 388-97.
There is an epidemiological association between increased obstetric
complications and disorders involving CNS dopamine dysregulation, such as
schizophrenia. In light of this, a rat model of global hypoxia during Caesarean
section (C-section) birth has been used to directly test if birth complications
can produce long-term dopaminergic dysregulation. Previous studies have shown
that, compared to vaginal birth, C-section birth alone (without additional
global hypoxia) is sufficient to increase D1-like receptor binding in rat brain
at adulthood. The current study examined (1) the developmental time course of
changes in D1-like or D2-like receptors following C-section birth; (2) whether
C-section birth from isoflurane-anesthetized dams also results in altered
D1-like receptor levels, as does C-section from decapitated dams; and (3)
behavioral responses to D1 and D2 agonists in rats born vaginally compared to
C-section. Increases in nucleus accumbens D1-like receptor binding due to
C-section birth were observed only at adulthood (3 months) but not prepubertally
(1 month or 2 weeks). D2-like receptor binding levels were unaffected by
C-section birth across the three developmental time points. Compared to vaginal
birth, D1-like receptors were increased following C-section birth from
isoflurane-anesthetized dams, as well as from decapitated dams. Adult rats that
had been born by C-section showed enhanced D1 potentiation of D2-induced
locomotor behavior. These studies indicate that C-section birth, from either
anesthetized or unanesthetized dams, results in postpubertal increases in
D1-like receptor binding and enhanced functional responses to D1 receptor
activation. (c) 2002 Elsevier Science (USA).
Bressan, R. A., D. C. Costa, et al. (2002). "Typical antipsychotic drugs - D(2)
receptor occupancy and depressive symptoms in schizophrenia." Schizophr Res
56(1-2): 31-6.
We tested the hypothesis that the degree of striatal dopamine D(2) receptor
blockade induced by typical antipsychotic treatment directly correlates with the
presence and severity of depressive symptoms in schizophrenia. Clinical and
[123I]-IBZM single-photon emission tomography (SPET) scan data obtained from 18
typical antipsychotic treated schizophrenic patients was analysed to evaluate
the relationship between striatal D(2) receptor occupancy and the depressive
subscale of the Brief Psychiatric Rating Scale (BPRS-D). Striatal D(2) receptor
occupancy by typical antipsychotic drugs was significantly positively correlated
with BPRS-D scores (r=0.52, p=0.025). This study suggests that high striatal
dopamine D(2) blockade by typical antipsychotic drugs may contribute to the
emergence of depressive symptoms in typical antipsychotic treated schizophrenic
patients.
Bullock, R. and S. Libretto (2002). "Risperidone in the treatment of psychoses
in the elderly: a case report series." Eur Psychiatry 17(2):
96-103.
Risperidone is one of the newer atypical antipsychotic agents, which combines
potent serotonin and dopamine receptor antagonism. It shows efficacy against the
positive and negative symptoms of schizophrenic psychoses and other psychotic
conditions, and has a low propensity to cause extrapyramidal side effects. The
aim of these case reports in elderly patients is to provide the benefit of
personal experience with risperidone to the body of published literature and to
demonstrate the types of patients that may benefit from treatment. These cases
were compiled retrospectively from data collected on referral and during routine
hospital appointments. This series covers four main areas of concern when
treating the elderly: low-maintenance dosing minimising the likelihood of
adverse events; successful treatment of patients previously uncontrolled and
experiencing side effects with other antipsychotics; the possibility of
intermittent rather than continuous treatment; and the benefits to patients,
carers and the health services. At low doses, risperidone is an effective and
well-tolerated treatment for psychoses in elderly patients that improves the
quality of life for both patients and their caregivers.
Caley, C. F. and C. K. Cooper (2002). "Ziprasidone: the fifth atypical
antipsychotic." Ann Pharmacother 36(5): 839-51.
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and
adverse effects of ziprasidone as a treatment for schizophrenia. DATA SOURCES:
Information was selected from a MEDLINE search (July 2000-October 2001) of
English-language medical literature using ziprasidone as the search term. Manual
searches of pertinent journal article references, request for medical
information from Pfizer, and access of the Web site of the Food and Drug
Administration were also performed. STUDY SELECTION: All available published
information regarding the pertinent characteristics of ziprasidone were
considered for selection. DATA EXTRACTION: Pharmacology and pharmacokinetic
studies were selected to provide a comprehensive description of these
characteristics. Clinical investigations were evaluated for design, sample size,
diagnosis, duration, and outcome. Data from all investigations were selected by
1 author and reviewed by both authors. DATA SYNTHESIS: Ziprasidone is a
benzisothiazolyl piperazine-type atypical antipsychotic that shares the
serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical
antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A)
receptor agonist and as a very weak inhibitor of serotonin and norepinephrine
reuptake. These data do not support ziprasidone as being a clinically meaningful
inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of
ziprasidone taken with food is approximately 60%, half-life is approximately 6-7
hours, and protein binding is extensive at >99%. Twelve metabolites have been
identified, yet only 4 of these are considered to be primary metabolites.
Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with
potential pharmacologic activity; CYP3A4 also contributes to the metabolism of
ziprasidone. Clinical studies support ziprasidone as efficacious for the
treatment of patients with acute exacerbations of schizophrenia or
schizoaffective disorder. Daily doses permitted in these clinical trials ranged
from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to
placebo. Future research efforts should be directed toward refractory
schizophrenia, cognitive impairment in schizophrenia, affective and anxiety
symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse
effect characteristics of ziprasidone commonly include headache, nausea, and
somnolence; infrequent effects include extrapyramidal symptoms and weight gain.
Ziprasidone has been reported to cause an average QTc prolongation of
approximately 20 msec; there have only been 2 patients (0.06%) reported by the
manufacturer to have a measured QTc interval >500 msec. CONCLUSIONS: Ziprasidone
is a safe and efficacious atypical antipsychotic for the acute management of
schizophrenia. Efficacy data and most safety data for ziprasidone support its
use as a first-line treatment for schizophrenia; however, its potential effects
on ventricular repolarization relegate it to second-line status in patients with
comorbid cardiovascular risks.
Capuano, B., I. T. Crosby, et al. (2002). "Schizophrenia: genesis, receptorology
and current therapeutics." Curr Med Chem 9(5): 521-48.
Schizophrenia is a debilitating mental disease affecting approximately 1% of the
population worldwide. Since the discovery of the first modern treatment for
schizophrenia, chlorpromazine, in 1952 there have been many new structures
investigated, only a small fraction of which have resulted in clinically useful
drugs. Of these, haloperidol may be regarded as the drug for first line
treatment. Since then, clozapine has emerged as the benchmark therapeutic
ameliorating positive and negative symptoms and devoid of movement disorders,
with its greatest feature being improvement of treatment-resistant patients.
However, a major, potential lethal side-effect of clozapine is the induction of
agranulocytosis, a blood disorder with unknown mechanism that results in lowered
white-blood cell counts and consequent susceptibility to infections. In the 50
years of antipsychotic drug development, several novel theories have evolved
that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4))
and the degree to which they need to be selectively attenuated by the drugs.
Also of significance is the location of these receptors in the brain in relation
to the disease state, the myriad of side-effects associated with antipsychotics
and physicochemical properties of antipsychotic molecules relative to models of
the drugs and the GPCR receptors involved. The techniques for investigation have
shown increasing sophistication and refinement over this period, involving
cloned receptors and PET scanning for determination of receptor location,
density and binding, and rate constants at receptors. Knowledge of receptor
structure, although in its infancy since no membrane bound CNS-receptor has yet
been crystallized, is likely to benefit substantially with advances in
computer-aided modelling. Overall, these new techniques have resulted in a
number of novel antipsychotics such as risperidone, sertindole, olanzapine,
seroquel, zotepine and ziprasidone, whose design, synthesis and testing has
benefited enormously from the accumulated knowledge base of the past 50 years.
In this review, we will provide a comprehensive update of the theories of action
and clinical profiles of the latest drugs listed. The following appraisal of the
literature will provide the practising medicinal chemist interested in this
critical area of research with sufficient insight and understanding, to embark
on productive investigations into the design and development of new therapeutic
agents devoid of clinically limiting side-effects.
Chen, L. and C. R. Yang (2002). "Interaction of dopamine D1 and NMDA receptors
mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal
cortex." J Neurophysiol 87(5): 2324-36.
The atypical antipsychotic drug clozapine effectively alleviates both negative
and positive symptoms of schizophrenia via unclear cellular mechanisms.
Clozapine may modulate both glutamatergic and dopaminergic transmission in the
prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole
cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal
neurons from rat PFC slices showed that stimulation of local afferents (in 2
microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA)
receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs).
Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold)
= -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The
potentiated EPSPs or rEPSPs were attenuated by elevating [Ca(2+)](O) (7 mM), by
application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50
microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1
microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion
(1 microM). Clozapine had no significant effect on pharmacologically isolated
evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without
changing the steady-state resting membrane potential. Under voltage clamp,
clozapine (1 microM) enhanced the frequency, and the number of low-amplitude
(5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such
changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest
that acute clozapine can increase spike-dependent presynaptic release of
glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors
to increase spontaneous EPSCs and enabled a voltage-dependent activation of
neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1
receptor to modulate a lasting potentiation of the NMDA receptor component of
the glutamatergic synaptic responses in the PFC neuronal network. This sequence
of early synaptic events induced by acute clozapine may comprise part of the
activity that leads to later cognitive improvement in schizophrenia.
Citver, A. S., A. M. Shields, et al. (2002). "Indirect modulation of dopamine D2
receptors as potential pharmacotherapy for schizophrenia: III. Retinoids." J
Clin Pharm Ther 27(3): 161-8.
Present antipsychotic drugs, whose clinical activity correlates with direct
binding to dopamine D2 or other receptors, alleviate some of the symptoms of
schizophrenia, but not all and not completely in many patients. In continuation
of our overview of potential novel antipsychotic pharmacotherapy that would be
based upon indirect modulation of dopamine or other neurotransmitter
functioning, we focus in this article on the postulated use of retinoid analogs
as novel antipsychotic agents. Several lines of evidence can be viewed as
implicating retinoid dysregulation in schizophrenia, either as a causative or
contributory factor. It has been proposed that using retinoid analogs to alter
the downstream expression of dopamine D2 receptors might represent a novel
approach to the treatment of the disease or amelioration of symptoms when used
either as monotherapy or as adjunct pharmacotherapy to dopamine D2 receptor
antagonists.
Curran, M. P. and C. M. Perry (2002). "Spotlight on amisulpride in
schizophrenia." CNS Drugs 16(3): 207-11.
Amisulpride, a substituted benzamide derivative, is a second-generation
(atypical) antipsychotic. At low doses, it enhances dopaminergic
neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3)
autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and
D(3) receptors, preferentially in the limbic system rather than the striatum,
thereby reducing dopaminergic transmission. In patients with acute exacerbations
of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day,
although dosages < or = 1200 mg/day may be administered. In comparative trials,
amisulpride administered within this range (400 to 1200 mg/day) was as effective
as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day
in patients with acute exacerbations of schizophrenia with predominantly
positive symptoms. Amisulpride was more effective than haloperidol but equally
effective as risperidone in controlling negative symptoms. Amisulpride 400 to
800 mg/day was more effective than haloperidol, risperidone and flupenthixol in
controlling affective symptoms in these patients. In randomised, double-blind
trials involving patients with predominantly negative symptoms of schizophrenia,
amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is
effective as maintenance therapy in patients with chronic schizophrenia.
Long-term treatment with amisulpride was associated with improvements in quality
of life and social functioning. Amisulpride is generally well tolerated. In
well-controlled trials, the neurological tolerability profile (including ratings
on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior
to that of the conventional antipsychotics (haloperidol or flupenthixol), but
was similar to that of the atypical antipsychotic risperidone. At low dosages of
amisulpride (< or = 300 mg/day), the incidence of adverse events (including
extrapyramidal symptoms) reported with amisulpride was similar to that with
placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day
showed efficacy in reducing overall symptomatology and positive symptoms similar
to that of conventional antipsychotics and newer atypical antipsychotics in
patients with acute exacerbations of schizophrenia. Moreover, its effective
alleviation of negative and affective symptoms, its lower association with
extrapyramidal symptoms and loss of cognitive function than conventional
antipsychotics and its long-term efficacy justifies consideration of the use of
higher dosages of amisulpride in this group of patients. Consequently, the
dosage of amisulpride that is recommended in patients with acute exacerbations
of schizophrenia is 400 to 800 mg/day, although dosages < or = 1200 mg/day may
be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be
considered for the management of patients with negative symptoms of
schizophrenia. Amisulpride is a first-line treatment option in the management of
schizophrenia in the acute phase and for the maintenance of treatment response.
Cyr, M., F. Calon, et al. (2002). "Estrogenic modulation of brain activity:
implications for schizophrenia and Parkinson's disease." J Psychiatry
Neurosci 27(1): 12-27.
Evidence suggests the estrogens may play a role in various mental and
neurodegenerative diseases. We review the evidence implicating estradiol in
schizophrenia and Parkinson's disease. Epidemiologic and clinical studies on the
effects of estrogens in schizophrenia are surveyed, and animal studies and in
vitro models of the modulatory effects of estrogens on neurotransmitters
associated with schizophrenia (i.e., dopamine, serotonin, glutamate) are
reviewed. Epidemiologic and clinical data suggesting a role for estrogens in
Parkinson's disease and in vivo and in vitro models demonstrating
neuroprotective effects of estrogens are then examined. Despite the numerous
animal studies on the effects of estrogens in the brain, clinical data are
sparse and often contradictory. Compounds with more specific and potent
estrogenic activity in the brain are required to further research efforts in
this area. Possible candidates are the selective estrogen receptor modulators (SERMs),
whose agonist or antagonist properties depend on the target tissue. The effects
of various SERMs in the brain are reviewed, and our novel findings on the
effects of SERMs on 5-HT2A receptors in the rat cortex and nucleus accumbens are
presented. We suggest that drugs with estrogenic activity in the brain may have
therapeutic potential, either by modulating brain neurotransmission or through
neuroprotective activity.
de Angelis, L. (2002). "5-HT2A antagonists in psychiatric disorders." Curr
Opin Investig Drugs 3(1): 106-12.
Several lines of evidence support a role for serotoninergic (5-HT) system
abnormalities in the pathogenesis and treatment of several psychiatric
disorders. This review summarizes information about the association between the
5-HT2A receptor gene and its relevance to schizophrenia, tardive dyskinesia,
major depression, suicidality, anorexia nervosa and obsessive-compulsive
disorder. Evidence is presented that implies that selective 5-HT2A antagonists
may be considered useful in investigating the role of 5-HT2A receptor function
and in the treatment of psychosis, and possibly alcohol and cocaine dependence.
Additionally, findings are reviewed on the importance of 5-HT2A receptor
antagonism in contributing to the therapeutic effect of several clinically
effective and potential atypical antipsychotics as well as several
antidepressants. In conclusion, the ability of selective 5-HT2A receptor
antagonists to interfere with the heightened state of dopamine activity without
altering basal tone, suggests that these drugs possess antipsychotic activity
and may provide the basis for new therapies for psychosis and drug dependence,
in addition to contributing towards a more complete understanding of 5-HT2A
receptor function.
de Paulis, T. (2002). "Perospirone (Sumitomo Pharmaceuticals)." Curr Opin
Investig Drugs 3(1): 121-9.
Perospirone is a serotonin 5-HT2 antagonist and dopamine D2 antagonist developed
by Sumitomo Pharmaceuticals for the potential treatment of schizophrenia and
other psychoses [381769]. Its receptor binding profile and animal pharmacology
resemble those of other atypical antipsychotic agents, in particular risperidone.
In November 2000, CPAC's First Committee on Drugs recommended the approval of
this product in Japan, [394007]; approval was granted in December 2000 [396121].
In January 2001, the NHI price was agreed by the Chuikyo [398222] and the drug
was added to the NHI price list in February 2001 13982261. It was finally
launched in Japan on February 8 2001 [399401]. In November 2000, Sumitomo and
Welfide signed an agreement whereby Welfide's subsidiary Yoshitomi Yakuhin will
copromote perospirone [394007]. Based on data from the Chuikyo, peak sales of
perospirone are forecast to be yen9 billion in the sixth year following launch
[398222], [398226]. In February 2001, Sumitomo predicted that perospirone would
reach sales of yen10 billion within five to six years [399401].
Dietrich, M., M. H. Hofmann, et al. (2002). "Effects of dopaminergic drugs and
telencephalic ablation on eye movements in the goldfish, Carassius auratus."
Brain Res Bull 57(3-4): 393-5.
The effect of the dopamine agonist apomorphine and the antagonist haloperidol on
eye movements was tested in normal and telencephalon ablated goldfish. Reflex
eye movements evoked by a rotating striped cylinder were not affected, which
suggests that basic sensory and motor functions were not influenced by neither
dopaminergic drugs nor the telencephalon. However, profound changes were
observed in spontaneous eye movements. Particularly, the effect of apomorphine
was similar to changes in eye movements observed in mammals after suppression of
dopaminergic functions either by means of drugs or in patients suffering from
Parkinson's disease or schizophrenia.
Eder, D. N. (2002). "CEE-03-310 CeNeS pharmaceuticals." Curr Opin Investig
Drugs 3(2): 284-8.
CEE-03-310 is a selective dopamine D1-like receptor antagonist with no
appreciable binding affinity for other receptors. Although originally developed
by Novo Nordisk A/S as NNC-687 for the treatment of schizophrenia, the company
changed its therapeutic focus in the mid-1990s and the full rights to CEE-03-310
and several related compounds were subsequently granted to CeNeS Pharmaceuticals
in 1999. CeNeS is currently investigating the drug's potential in the treatment
of insomnia and alcohol dependency [340965], [382293], [401496],[416026]. A
phase II, double-blind, placebo-controlled trial of CEE-03-310 demonstrated a
dose-dependent enhancement of NREM sleep at the beginning of the night without
any effects on the quantity of REM sleep [410739].
Elkashef, A. M., H. Al-Barazi, et al. (2002). "Dopamine effect on the
mitochondria potential in B lymphocytes of schizophrenic patients and normal
controls." Prog Neuropsychopharmacol Biol Psychiatry 26(1): 145-8.
Brain metabolic abnormalities and aberrant dopamine (DA) metabolism have been
reported in patients with schizophrenia. The authors hypothesized that
mitochondria is a primary target of damage by increased free radical generation
secondary to increased DA metabolism by monoamine oxidase (MAO). Epstein-Barr
virus (EBV)-transformed human B-lymphocytes cell lines derived from patients
with schizophrenia and normal controls were incubated in the absence or presence
of DA, hydrogen peroxide (H2O2), or rotenone (Rot). The cells were then stained
with rhodamine 123 (Rh 123) and analyzed for uptake using flow cytometry.
Compared with untreated cells, DA significantly decreased Rh 123 uptake by the
mitochondria. This effect was similar to the control cells treated with H2O2 or
Rot. Nevertheless, there were no differences in Rh 123 uptake between the cells
of schizophrenic patients and normal controls. This study shows that DA can
impair the mitochondria membrane potential but that mechanism may not be evident
in schizophrenia.
George, T. P., J. C. Vessicchio, et al. (2002). "Effects of smoking abstinence
on visuospatial working memory function in schizophrenia."
Neuropsychopharmacology 26(1): 75-85.
Schizophrenic patients have impairments in cognitive function, including
deficits in visuospatial working memory (VSWM). VSWM is mediated, in part, by
prefrontal cortical dopamine (DA) function, and dysregulation of prefrontal
cortical DA systems may contribute to the pathophysiology of schizophrenia.
Nicotine has complex effects on spatial working memory (SWM) in animal studies,
with most studies demonstrating enhancement of SWM. Cigarette smoking is highly
prevalent in schizophrenia, and these patients may smoke cigarettes to remediate
cognitive deficits. The present study examined the effects of acute (<1 week)
and prolonged (8-10 weeks) smoking abstinence on VSWM in schizophrenic (n = 23)
and control (n = 29) nicotine-dependent cigarette smokers during
placebo-controlled smoking cessation trials. Schizophrenic and control smoking
patients had significant impairments in VSWM compared to non-smoking controls,
after adjusting for differences in age, education and depressive symptoms.
Schizophrenic smokers who quit smoking had further impairments in VSWM, and
control quitters had improvements in VSWM. Abstinence-induced changes in VSWM
varied as a function of gender in controls, but not in schizophrenics. These
changes in VSWM appeared to be independent of study medications, and smoking
abstinence did not significantly alter performance on the Stroop Color Word Test
in either group. These results suggest that smoking abstinence differentially
alters VSWM in schizophrenic vs. control smokers, and that cigarette smoking has
beneficial effects on VSWM in schizophrenic, but not control, smokers.
Georgieva, L., A. Dimitrova, et al. (2002). "Dopamine transporter gene (DAT1)
VNTR polymorphism in major psychiatric disorders: family-based association study
in the Bulgarian population." Acta Psychiatr Scand 105(5): 396-9.
OBJECTIVE: A 40-bp variable number tandem repeat in the 3'-UTR of dopamine
transporter gene (DAT1) has been examined for association with major psychiatric
disorders in several case-control studies. No significant results have been
found. We used a new collection of parent-offspring trios to test for
association with schizophrenia (SZ), bipolar 1 disorder (BPI) and
schizoaffective (SA) disorder. METHOD: We genotyped trios from Bulgarian origin
where the proband had SZ (178 trios), BPI (77 trios) and SA (29 trios). Alleles
ranging from 5 to 11 repeats were observed. The results were analysed with the
extended TDT (ETDT). RESULTS: No preferential transmission of alleles was
observed for any diagnostic group. The presence of allele DAT*10 was associated
with the severity and frequency of auditory hallucinations, however, this result
is not significant if corrected for multiple testing. CONCLUSION: Our results
are in agreement with previous reports of a lack of association between this
polymorphism and major psychiatric disorders.
Gijsman, H. J., A. Scarna, et al. (2002). "A dose-finding study on the effects
of branch chain amino acids on surrogate markers of brain dopamine function."
Psychopharmacology (Berl) 160(2): 192-7.
RATIONALE: We have previously shown in healthy volunteers that an amino acid
mixture lacking tyrosine and phenylalanine reduces tyrosine availability to the
brain and produces cognitive and neuroendocrine effects consistent with reduced
dopamine function. This could provide a potential nutritional approach to
disorders such as mania and schizophrenia, which are characterised by
overactivity of dopamine pathways. The amino acid mixture we tested previously
is unpalatable, whereas mixtures containing only branch chain amino acids can be
made more palatable. However, the effects of such mixtures on dopamine function
in humans have not been studied. OBJECTIVE: To assess the tolerability of
different doses of branch chain amino acids and to measure their effects on
neuroendocrine and cognitive measures sensitive to changes in dopamine function.
METHODS: We used a randomised, double-blind, cross-over design in 12 healthy
volunteers to assess the effect of single oral doses of 10 g, 30 g and 60 g
branch chain amino acids on plasma prolactin and a test of spatial recognition
memory RESULTS: The branch chain amino acids were well tolerated. The
availability of tyrosine for brain catecholamine synthesis decreased in a
dose-related manner. As hypothesised, the drink increased both the plasma
prolactin and the latency to respond on the spatial recognition memory task.
CONCLUSIONS: A drink containing branch chain amino acids is well tolerated in
healthy volunteers and produces effects consistent with lowered dopamine
function.
Golimbet, V. E., M. G. Aksenova, et al. (2002). "[Linkage sib-pair analysis of
dopamine receptor D2 gene Taq1A and Taq1B polymorphism and schizophrenia]."
Zh Nevrol Psikhiatr Im S S Korsakova 102(4): 43-4.
Gracey, D. J., R. Bell, et al. (2002). "Differential effects of the CCK(A)
receptor ligands PD-140,548 and A-71623 on latent inhibition in the rat."
Prog Neuropsychopharmacol Biol Psychiatry 26(3): 497-504.
Latent inhibition (LI) is a behavioural paradigm in which repeated exposure to a
stimulus without consequence inhibits the formation of any new associations with
that stimulus. To the extent that LI reflects a process of leaming to ignore
irrelevant stimuli, disrupted LI has been suggested as an animal model for the
attentional deficits observed in schizophrenia. The antipsychotic potential of
cholecystokinin (CCK) stems from its colocalization with dopamine (DA) in the
mesolimbic pathway, where it demonstrates both excitatory and inhibitory effects
on dopaminergic activity. This may be explained by mediation through different
receptor subtypes. A variety of hypotheses has emerged regarding the potential
clinical application of subtype-selective CCK-based drugs. The present
experiments examined the effects on LI of two selective CCK(A) ligands:
PD-140,548 (a CCK(A) antagonist, Experiment 1: 0.001, 0.01, and 0.1 mg/kg) and
A-71623 (a CCK(A) agonist, Experiment 2: 0.02, 0.05, and 0.1 mg/kg). In both
experiments, the effects of haloperidol (0.1 mg/kg) were also investigated.
Animals receiving 0.1 mg/kg of haloperidol or 0.001 or 0.1 mg/kg (but not 0.01
mg/kg) of PD-140,548 treated the preexposed stimulus as irrelevant after a low
number of preexposures. In contrast, no facilitatory effect on LI was detectable
at any of the A-71623 doses. The finding that A-71623 failed to enhance LI
indicates that it is unlikely that this compound would have any antipsychotic
effect within the clinical setting. Considering the facilitatory effect exerted
by PD-140,548 on LI, it is probable that the inhibition of CCK activity might
prove a more promising strategy for the pharmacological treatment of
schizophrenia.
Heinz, A. (2002). "Dopaminergic dysfunction in alcoholism and schizophrenia -
psychopathological and behavioral correlates." Eur Psychiatry 17(1):
9-16.
Dysfunction of central dopaminergic neurotransmission has been implicated in the
pathogenesis of schizophrenia as well as drug and alcohol dependence. Different
drugs of abuse stimulate dopamine release in the ventral striatum and thus
reinforce drug consumption. Increased subcortical dopamine release has also been
associated with the pathogenesis of positive symptoms in schizophrenia and may
be driven by a prefrontal dopaminergic dysfunction. These seemingly
heterogeneous findings may be explained by recent research in non-human
primates. According to these studies, reward anticipation but not anticipated
reward consumption is accompanied by a phasic dopamine release in the striatum
and prefrontal cortex. In the striatum, phasic dopamine release primarily
affects motivation, psychomotor activation and reward craving, while in the
prefrontal cortex, dopaminergic stimulation is involved in the activation of
working memory and reward anticipation. In alcoholism, previously neutral
stimuli that have been associated with alcohol intake can become conditioned
cues which activate phasic dopamine release and reward craving. In
schizophrenia, stress-induced or chaotic activation of dopamine release may
attribute incentive salience to otherwise irrelevant stimuli and thus be
involved in the pathogenesis of delusional mood and other positive symptoms.
Studies in humans and non-human primates emphasize the role of dopaminergic
neurotransmission in reward anticipation and its dysfunction in different
neuropsychiatric diseases.
Hillion, J., M. Canals, et al. (2002). "Coaggregation, cointernalization, and
codesensitization of adenosine A2A receptors and dopamine D2 receptors." J
Biol Chem 277(20): 18091-7.
Antagonistic and reciprocal interactions are known to exist between adenosine
and dopamine receptors in the striatum. In the present study, double
immunofluorescence experiments with confocal laser microscopy showed a high
degree of colocalization of adenosine A(2A) receptors (A(2A)R) and dopamine D(2)
receptors (D(2)R) in cell membranes of SH-SY5Y human neuroblastoma cells stably
transfected with human D(2)R and in cultured striatal cells. A(2A)R/D(2)R
heteromeric complexes were demonstrated in coimmunoprecipitation experiments in
membrane preparations from D(2)R-transfected SH-SY5Y cells and from mouse
fibroblast Ltk(-) cells stably transfected with human D(2)R (long form) and
transiently cotransfected with the A(2A)R double-tagged with hemagglutinin. Long
term exposure to A(2A)R and D(2)R agonists in D(2)R-cotransfected SH-SY5Y cells
resulted in coaggregation, cointernalization and codesensitization of A(2A)R and
D(2)R. These results give a molecular basis for adenosine-dopamine antagonism at
the membrane level and have implications for treatment of Parkinson's disease
and schizophrenia, in which D(2)R are involved.
Himei, A., J. Koh, et al. (2002). "The influence on the schizophrenic symptoms
by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms." Psychiatry Clin
Neurosci 56(1): 97-102.
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.
Ishihara, K. and M. Sasa (2002). "[Modulation of neuronal activities in the
central nervous system via sigma receptors]." Nihon Shinkei Seishin
Yakurigaku Zasshi 22(1): 23-30.
Sigma receptors have recently been the target of drug development related to
psychiatric disorders, including schizophrenia and depression, as well as
cognitive enhancers. This paper focused on the sigma-receptor-mediated
modulation of neuronal activity, especially the effects on aminergic neuron and
hippocampal neuron activity. Dopaminergic neuron activities in the substantia
nigra and ventral tegmental area (VTA) are variously modified by the systemic
administration of sigma ligands. When applied with microiontophoresis, they are
reported to increase dopaminergic neuron activity in the VTA. This activity may
be involved in the psychotropic or antipsychotic effects of these ligands.
Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in
the locus coeruleus were activated by sigma ligands. These effects are probably
related to the antidepressant activity of sigma receptor ligands. In the
hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The
effects were suggested to be due to an increase in the threshold of action
potential and decreased synaptic transmission efficacy. NMDA receptor function
was modified in biphasic fashion related to doses of sigma ligands, that is, a
lower dose facilitated the NMDA receptor functions, and a higher dose inhibited
them. These effects on the hippocampal neurons may contribute to their
neuroprotective and antiamnesic actions. Further studies are needed to elucidate
the relation between the physiological function of sigma receptor and
psychiatric diseases by the use of sigma receptor ligands and molecular
techniques.
Ito, C. (2002). "Analysis of overall gene expression induced by amphetamine and
phencyclidine: novel targets for the treatment of drug psychosis and
schizophrenia." Curr Pharm Des 8(2): 147-53.
Although the etiology of drug psychosis or schizophrenia is still unknown,
molecular and biochemical researches have recently made significant advances in
the search for the candidate genes of these disorders. Among such studies are
animal models of drug psychosis or schizophrenia such as amphetamine-induced
behavioral sensitization or phencyclidine-treated animals. In this review, it is
suggested that amphetamine or phencyclidine change the gene expressions related
to not only neurotransmitter systems such as dopamine or glutamic acid,
transcription factors, cell proliferation, apoptosis, cell adhesion, but also
the synapse. These alterable gene expressions may lead to the discovery of
candidate genes of drug psychosis or schizophrenia and thus to novel
antipsychotics.
Jardemark, K., M. L. Wadenberg, et al. (2002). "Dopamine D3 and D4 receptor
antagonists in the treatment of schizophrenia." Curr Opin Investig Drugs
3(1): 101-5.
The findings that dopamine D3 and D4 receptors are highly expressed in limbic
and cortical areas (D4 more than D3), and the fact that the atypical drug
clozapine has preferential affinity for the D4 receptors have suggested an
involvement of these receptors in schizophrenia. Subsequently, many
pharmaceutical companies have pursued the approach of developing selective
dopamine D3 or D4 antagonists as potential antipsychotics. This review will
discuss the current status of selective dopamine D3 and D4 receptor antagonists
for the treatment of schizophrenia.
Jin, G. Z., Z. T. Zhu, et al. (2002). "(-)-Stepholidine: a potential novel
antipsychotic drug with dual D1 receptor agonist and D2 receptor antagonist
actions." Trends Pharmacol Sci 23(1): 4-7.
Jordan, S., V. Koprivica, et al. (2002). "The antipsychotic aripiprazole is a
potent, partial agonist at the human 5-HT(1A) receptor." Eur J Pharmacol
441(3): 137-140.
Aripiprazole,
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2(1H)-qui
nolinone, a novel antipsychotic with partial agonist activity at dopamine D2
receptors, bound with high affinity to recombinant human 5-HT(1A) receptors
(h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent,
partial agonism at 5-HT(1A) receptors in a
guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS)-binding assay that
was blocked completely by a selective 5-HT(1A) receptor antagonist. An
interaction with 5-HT(1A) receptors may contribute to the overall efficacy of
aripiprazole against symptoms of schizophrenia, including anxiety, depression,
cognitive and negative symptoms, and to its favorable side-effect profile.
Combined with previous studies demonstrating the potent partial agonism of
aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the
first dopamine-serotonin system stabilizer.
Kapur, S., R. A. McClelland, et al. (2002). "Increasing D2 affinity results in
the loss of clozapine's atypical antipsychotic action." Neuroreport 13(6):
831-5.
Typical antipsychotics (haloperidol) give rise to severe motor side-effects
while atypical antipsychotics like clozapine do not. Action at several
neurotransmitter receptors have been implicated. To identify the critical
mechanisms involved we synthesized an 8-C1 isomer of clozapine which showed an
equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4,
M1) but differed in having a 10-fold higher affinity at the dopamine D2/3
receptor. When tested in a series of animal models indicative of the
typical/atypical distinction (catalepsy, striatal gene-induction, prolactin
elevation) isoclozapine lost atypical properties and behaved like a typical
antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that
alterations in D2 receptor occupancy were most closely related to loss of
atypicality by clozapine's isomer isoclozapine. The implications for the design
of future antipsychotics is discussed.
Karlsson, P., L. Farde, et al. (2002). "PET study of D(1) dopamine receptor
binding in neuroleptic-naive patients with schizophrenia." Am J Psychiatry
159(5): 761-7.
OBJECTIVE: Postmortem studies and a positron emission tomography (PET) study
have suggested that there is a disturbance of central D(1) dopamine receptor
function in schizophrenia. The objective of the present PET study was to compare
D(1) receptor binding in first-admission, neuroleptic-naive patients with
schizophrenia and in healthy subjects. METHOD: Ten healthy comparison subjects
and 10 neuroleptic-naive patients with schizophrenia (diagnosed according to
DSM-III-R) were examined twice by PET using (11)C-labeled SCH 23390 ([(11)C]SCH
23390) with high and low specific radioactivity, respectively. The binding
potential, receptor density (B(max)), and affinity (K(d)) were determined for
the caudate nucleus, the putamen, and several neocortical regions during both
PET examinations. Scatchard plots from the two measurements were used to
calculate regional D(1) B(max) and K(d). The regional binding values were tested
for hemispheric asymmetry and for correlation to clinical symptoms measured by
the Brief Psychiatric Rating Scale (BPRS). RESULTS: [(11)C]SCH 23390 binding to
D(1) receptors did not differ significantly between subjects with schizophrenia
and healthy subjects in any of the brain regions or for any of the binding
measures studied. Asymmetry of the regional binding values did not differ
significantly between the two groups. Scores on the BPRS negative symptom
subscale correlated significantly with the B(max) in the right frontal cortex.
CONCLUSIONS: These results do not replicate previous postmortem and PET findings
of altered central dopamine D(1) receptor binding in schizophrenia. The finding
of a positive correlation between frontal D(1) binding and scores on the
negative symptom subscale of the BPRS is contrary to a previously reported
finding of a negative correlation. These discrepancies motivate further studies
using D(1) ligands with higher signals for cortical regions.
Keri, S., Z. Janka, et al. (2002). "Early-stage vision and schizophrenia." Am
J Psychiatry 159(4): 678; discussion 678-9.
Leucht, S., G. Pitschel-Walz, et al. (2002). "Amisulpride, an unusual "atypical"
antipsychotic: a meta-analysis of randomized controlled trials." Am J
Psychiatry 159(2): 180-90.
OBJECTIVE: The "atypical" profile of the new antipsychotics clozapine,
olanzapine, quetiapine, and risperidone has been linked to combined antagonism
of serotonin 2 (5-HT(2)) and dopamine 2 (D(2)) receptors. Although amisulpride
is a highly selective D(3)/D(2) receptor antagonist, it is assumed to have
atypical properties as well. The purpose of this article was to compare the
atypical profile of amisulpride with that of the 5-HT(2)/D(2) antagonists.
METHOD: Randomized controlled trials that compared amisulpride with conventional
antipsychotics or placebo for patients with schizophrenia were identified and
included in a meta-analysis. The mean effect sizes found for amisulpride were
compared with those of an updated meta-analysis of the 5-HT(2)/D(2) antagonists.
RESULTS: Eighteen randomized controlled trials of amisulpride (N=2,214) were
found. In 11 studies of acutely ill patients it proved to be consistently more
effective than conventional antipsychotics for global schizophrenic symptoms
(measured with the Brief Psychiatric Rating Scale) and negative symptoms.
Amisulpride is to date the only atypical antipsychotic for which several studies
of patients suffering predominantly from negative symptoms have been published.
In four such studies amisulpride was significantly more effective than placebo.
Three small studies with conventional antipsychotics as comparators showed only
a trend in favor of amisulpride in this regard. Amisulpride was associated with
clearly lower use of antiparkinsonian medication and with fewer dropouts due to
adverse events than conventional antipsychotics. CONCLUSIONS: These results cast
some doubt on the notion that combined 5-HT(2)/D(2) antagonism is the reason
that the newer antipsychotic medications are effective for negative symptoms and
have fewer extrapyramidal side effects.
Lipska, B. K., N. D. Halim, et al. (2002). "Effects of reversible inactivation
of the neonatal ventral hippocampus on behavior in the adult rat." J Neurosci
22(7): 2835-42.
Rats with neonatal excitotoxic damage of the ventral hippocampus display in
adulthood a variety of abnormalities reminiscent of schizophrenia and are used
as an animal model of this disorder. In the present study, we hypothesized that
transient inactivation of ventral hippocampal activity during a critical
developmental period may be sufficient to disrupt normal maturation of relevant
brain systems and produce similar lasting behavioral changes. We infused
tetrodotoxin (TTX) or artificial CSF into the ventral hippocampus on postnatal
day 7 (P7) and assessed behavioral changes in response to stress, amphetamine,
and (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate
in juvenile (P35) and young adult (P56) rats. In adulthood, rats infused
neonatally with TTX displayed motor hyperactivity after pharmacological
stimulation and after stress compared with sham controls. Analogous TTX
infusions in adult animals did not alter these behaviors later in life. These
data suggest that transient loss of ventral hippocampal function during a
critical time in maturation of intracortical connections permanently changes the
development of neural circuits mediating certain dopamine- and NMDA-related
behaviors. These results represent a potential new model of aspects of
schizophrenia without involving a gross anatomic lesion.
Mattsson, A., S. O. Ogren, et al. (2002). "Facilitation of dopamine-mediated
locomotor activity in adult rats following cholinergic denervation." Exp
Neurol 174(1): 96-108.
The dopamine hypothesis of schizophrenia postulates hyperactivity of
dopaminergic neurotransmission in the mesolimbic system. However, the possible
underlying causes for this dopaminergic overfunction are not well understood.
Therefore, the main aim of this study was to examine the effect of central
cholinergic denervation on dopamine-mediated functions. We also examined the
effect of neonatal cholinergic denervation upon adult brain function. The
immunotoxin 192 IgG-saporin causes severe lesions of the basal forebrain
cholinergic system when infused into the lateral ventricles by targeting neurons
expressing the p75 neurotrophin receptor. The toxin may also damage
p75-expressing Purkinje neurons in the cerebellum. We have compared the
behavioral effects of intracerebroventricular injections of 192 IgG-saporin to
adult rats with that of injections to neonate rats. As expected, adult treated
rats displayed an almost complete cholinergic denervation of forebrain
corticohippocampal areas concomitant with a marked impairment in the Morris
water maze. When tested as adults, neonatally treated animals had a less
complete cholinergic denervation and showed lesser impairments in water maze
behaviors. Interestingly, adult treated rats showed increased spontaneous
horizontal activity and a remarkable increase in locomotor response to
d-amphetamine as evidenced by increased horizontal and vertical activity. There
were no marked changes of spontaneous or drug-induced locomotor activity in
adult rats treated with 192 IgG-saporin as neonates. These results suggest that
cholinergic denervation of the forebrain causes a marked enhancement of
behavioral responses related to dopaminergic activity, probably mainly mediated
presynaptically. However, it cannot be fully excluded that damage to
noncholinergic systems, e.g., Purkinje cells, might contribute to the effects.
The striking overreaction to dopaminergic stimuli, presumably caused by the
cholinergic deficit, is discussed in relation to the suggested role of
cholinergic malfunctioning in schizophrenia.
Mazei, M. S., C. P. Pluto, et al. (2002). "Effects of catecholamine uptake
blockers in the caudate-putamen and subregions of the medial prefrontal cortex
of the rat." Brain Res 936(1-2): 58-67.
Altered dopamine regulation in the medial prefrontal cortex has been linked to
drug abuse and disorders such as schizophrenia. Heterogeneous expression of the
dopamine transporter, as well as the ability of the norepinephrine transporter
to clear dopamine in the prefrontal cortex, delineates two potential sites for
the regulation of synaptic dopamine within the cortex. The present study used in
vivo microdialysis to compare the effects of local infusions of dopamine and
norepinephrine uptake blockers in the caudate putamen and two subregions of the
prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices.
Results revealed that all dopamine uptake blockers produced greater increases in
dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In
addition, amphetamine administration increased dopamine efflux to a greater
degree in the prelimbic, relative to the anterior cingulate, cortex. In
contrast, the increase in dopamine efflux was similar in both subregions in the
presence of nomifensine and desmethylimipramine. Infusions of the selective
dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any
prefrontocortical subregion. These data indicate a more prominent role for the
dopamine transporter in the clearance of extracellular dopamine in the
caudate-putamen relative to the prefrontal cortex and an important role for NET
in the clearance of dopamine in both the prelimbic and anterior cingulate
subregions of the rat medial prefrontal cortex.
Meyer-Lindenberg, A., R. S. Miletich, et al. (2002). "Reduced prefrontal
activity predicts exaggerated striatal dopaminergic function in schizophrenia."
Nat Neurosci 5(3): 267-71.
Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are
known to be abnormal in schizophrenia. To test the hypothesis that these
phenomena are related, we measured presynaptic dopaminergic function
simultaneously with regional cerebral blood flow during the Wisconsin Card
Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and
matched controls. We show that the dopaminergic uptake constant Ki in the
striatum was significantly higher for patients than for controls. Patients had
significantly less WCST-related activation in PFC. The two parameters were
strongly linked in patients, but not controls. The tight within-patient coupling
of these values, with decreased PFC activation predicting exaggerated striatal
6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction
may lead to dopaminergic transmission abnormalities.
Moghaddam, B. (2002). "Stress activation of glutamate neurotransmission in the
prefrontal cortex: implications for dopamine-associated psychiatric disorders."
Biol Psychiatry 51(10): 775-87.
In most psychiatric disorders, stress is the major nongenomic factor that
contributes to the expression or exacerbation of acute symptoms, recurrence or
relapse after a period of remission, and treatment outcome. Delineation of
mechanisms by which stress contributes to these processes is fundamental to
understanding the disease process and for improving outcome. In this article,
evidence is reviewed to indicate that many central aspects of stress response,
including activation of the hypothalmic-pituitary-adrenal (HPA) axis and
dopamine neurotransmission, are modulated, and in some cases mediated, by
glutamate neurotransmission in the prefrontal cortex (PFC). It is suggested that
activation of glutamatergic neurotransmission in the PFC presents a common
mechanism by which stress influences normal and abnormal processes that sustain
affect and cognition. Although monoamines, in particular dopamine, have been
considered the major culprits in the adverse effects of stress in disorders such
as addiction and schizophrenia, it is likely that in a vulnerable brain with an
underlying PFC pathophysiology, abnormal stress-activated monoaminergic
neurotransmission is secondary to anomalies in cortical glutamate
neurotransmission. Thus, understanding the contribution of glutamate-mediated
processes to stress response through the use of experimental models that involve
disrupted PFC function can provide insights to the fundamental pathophysiology
of stress-sensitive psychiatric disorders and lead to novel strategies for
treatment and prevention.
Morimoto, K., R. Miyatake, et al. (2002). "Delusional disorder: molecular
genetic evidence for dopamine psychosis." Neuropsychopharmacology 26(6):
794-801.
Since delusional disorder is characterized by mono-symptomatic paranoid
symptoms, it can be a good clinical model for investigating the dopaminergic
mechanism responsible for paranoid symptoms. We examined neuroleptic responses,
plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its
synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional
disorder and compared them with those of schizophrenic patients and healthy
controls. RESULTS: (1) A relatively small dose of haloperidol was more effective
for delusional disorder than for schizophrenia. (2) The pretreatment level of
pHVA was higher in patients with persecution-type, but not in those with
jealousy-type delusional disorder, compared with age- and sex-matched controls.
This increased pHVA level was decreased eight weeks after successful haloperidol
treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was
significantly higher in patients with persecution-type delusional disorder
(21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients
homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than
those heterozygous for Ser9Gly. (v) A significant positive correlation was found
between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and
pretreatment levels of pHVA in delusional disorder. We suggest that delusional
disorder, especially the persecution-type, includes a "dopamine psychosis," and
that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis
underlying the hyperdopaminergic state that produces paranoid symptoms. Further
studies on a large sample size are required.
Neuhoff, H., A. Neu, et al. (2002). "I(h) channels contribute to the different
functional properties of identified dopaminergic subpopulations in the
midbrain." J Neurosci 22(4): 1290-302.
Dopaminergic (DA) midbrain neurons in the substantia nigra (SN) and ventral
tegmental area (VTA) are involved in various brain functions such as voluntary
movement and reward and are targets in disorders such as Parkinson's disease and
schizophrenia. To study the functional properties of identified DA neurons in
mouse midbrain slices, we combined patch-clamp recordings with either
neurobiotin cell-filling and triple labeling confocal immunohistochemistry, or
single-cell RT-PCR. We discriminated four DA subpopulations based on anatomical
and neurochemical differences: two calbindin D28-k (CB)-expressing DA
populations in the substantia nigra (SN/CB+) or ventral tegmental area
(VTA/CB+), and respectively, two calbindin D28-k negative DA populations
(SN/CB-, VTA/CB-). VTA/CB+ DA neurons displayed significantly faster pacemaker
frequencies with smaller afterhyperpolarizations compared with other DA neurons.
In contrast, all four DA populations possessed significant differences in I(h)
channel densities and I(h) channel-mediated functional properties like sag
amplitudes and rebound delays in the following order: SN/CB- --> VTA/CB- -->
SN/CB+ --> VTA/CB+. Single-cell RT-multiplex PCR experiments demonstrated that
differential calbindin but not calretinin expression is associated with
differential I(h) channel densities. Only in SN/CB- DA neurons, however, I(h)
channels were actively involved in pacemaker frequency control. In conclusion,
diversity within the DA system is not restricted to distinct axonal projections
and differences in synaptic connectivity, but also involves differences in
postsynaptic conductances between neurochemically and topographically distinct
DA neurons.
Nguimfackmbodie, P. C. (2002). "[Do the glutamate excitotoxicity theory and
potential free radicals implication in schizophrenia aetiopathogenesis provide a
new enlightenment to links between: genome, environment and biology in the
determinism of that disorder?]." Encephale 28(2): 147-53.
The aetiopathogenesis of schizophrenia constitutes nowadays one of the major
points of interest for researchers on this cosmopolitan disorder which involves
about 1% of the world population and which significantly alters the social
functioning of the individual. Numerous studies have focused on the role played
by genome, environmental factors and biology in the development of symptoms. The
neurodevelopmental theory is an illustration with the perinatal period
considered as the main provider of environmental factors (hypertension,
infections, bleedings during pregnancy, acute and chronic fetal distress.). Many
authors found significant associations between such factors, the occurrence of
brain lesions and finally schizophrenic symptoms. Although no convincing genetic
model had been established to date for schizophrenia, nevertheless it appears
that a predisposition not inheritable under the mendelian mode exists and
authors showed that disease gets more and more severe over schizophrenic
descendants. The risk to be schizophrenic being a first degree relative of the
schizophrenic person is about ten time superior than in general population.
Indeed, this risk is also about ten time superior in biological parents of
schizophrenic adoptees than in biological parents of healthy adoptees. Studies
done in monozygotic comparing to dizygotic twins are in favour of an important
role played by genetic factors more than socioeducational or psychological
factors. Concerning biology, the dopaminergic hypothesis remains shared by
numerous authors although direct links with incriminated factors are not well
established. Now is suspected the glutamate excitotoxicity with implication of
free radicals in schizophrenia. These free radicals are products of various
enzymatic activations led by overstimulation of post synaptic receptors (NMDA
and AMPA) by the excess glutamate. Therefore, according to that concept, some
amino acids as glutamate and derivatives could have through free radicals a
noxious effect on neuronal synapses. This could be due to a failing of their
recapture at the presynaptic level in addition to a dysfunctioning of the
antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to
which dopamine and other monoamines might participate. The question is whether
or not this theory contributes to shed light on links between: genome,
environmental factors and biology in schizophrenia. Through the review and
discussion of genetical aspects of schizophrenia, environmental factors and the
biological aspect, we intend to revive debate on that question. The articles and
authors were selected with regard to the aptness of their publications on that
subject, their evolving ideas and finally the interest of their works for
neurosciences. This new approach perhaps is opening the way to new therapeutic
perspectives in the treatment of schizophrenia based on the antioxidizing
substances as shown for some neurological diseases (amyotrophic lateral
sclerosis, Parkinson's disease and Huntington's chorea) for which experiments
are going on.
Nocjar, C., B. L. Roth, et al. (2002). "Localization of 5-HT(2A) receptors on
dopamine cells in subnuclei of the midbrain A10 cell group." Neuroscience
111(1): 163-76.
Considerable evidence suggests that a dysfunction of the dopamine and serotonin
(5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse
range of pathological conditions including schizophrenia, depression and drug
abuse. Recent electrophysiological and behavioral studies suggest that 5-HT
modulates dopaminergic neurons in the ventral tegmental area via activation of
5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their
actions on dopaminergic neurons in the ventral tegmental area via direct or
indirect mechanisms. This study investigated whether 5-HT(2A) receptors were
localized on dopamine cells within the A10 dopamine subnuclei of the rat,
including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like
immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine
neurons, throughout the A10 dopamine cell population. Colocalization was most
prominent in rostral and mid A10 regions, including the paranigral,
parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic
neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral
tegmental area. Additionally, although a dense population of 5-HT(2A)
immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely
were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10
dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and
tyrosine hydroxylase colocalization.These findings provide an anatomical basis
for the physiological modulation of dopamine neurons in the rostral ventral
tegmental area either directly, by 5-HT(2A) receptors localized on dopamine
cells, or indirectly, through a non-dopaminergic mechanism. Interestingly,
5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei
that project to mesolimbic forebrain regions implicated in drug addiction, and
recent evidence indicates that ventral tegmental area 5-HT(2A) receptor
activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors
were also expressed on dopamine cells in A10 subnuclei that project to forebrain
areas that have been implicated in schizophrenia, and atypical antipsychotic
drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study
could have important implications for understanding 5-HT and dopamine circuitry
dysfunction in schizophrenia.
Ozdemir, V., J. Fourie, et al. (2002). "Aripiprazole (Otsuka Pharmaceutical
Co)." Curr Opin Investig Drugs 3(1): 113-20.
Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing
aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor
antagonist, for the potential treatment of psychoses including schizophrenia
[281327], [340364]. A regulatory filing for schizophrenia in the US was
submitted at the end of 2001 [340364]. The compound entered phase III trials in
Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may
be efficacious in the treatment of schizophrenia, they may also potentially
increase the risk for exacerbation of psychosis through stimulation of
postsynaptic dopaminergic receptors [245791], [350478], [350479]. However,
earlier neuropharmacology studies have shown that aripiprazole can act as a
presynaptic D2 agonist while displaying an antagonistic effect at the
postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In
animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without
causing catalepsy [281327], [337126]. Moreover, in contrast to classical
antipsychotics that produce disabling movement disorders, aripiprazole does not
cause an upregulation of D2 receptors or an increase in expression of the c-fos
mRNA in the striatum, in agreement with the low risk for extrapyramidal side
effects (EPS) during aripiprazole treatment [245781], [262096], [350481],
[350483]. Collectively, aripiprazole is an important atypical antipsychotic
candidate with a favorable safety profile. Moreover, the mechanism of action of
aripiprazole differentiates it from both typical and atypical antipsychotics and
hence, may provide important leads for pharmacotherapy of schizophrenia and
other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales
of aripiprazole could reach US $500 million [357788]. In February 2001, Credit
Suisse First Boston predicted sales of US $403 million in 2005 [399484].
Pani, L. and G. L. Gessa (2002). "The substituted benzamides and their clinical
potential on dysthymia and on the negative symptoms of schizophrenia." Mol
Psychiatry 7(3): 247-53.
In this paper the historical and scientific background that led to the use of
substituted benzamides in two apparently unrelated clinical conditions namely
dysthymic disorder and schizophrenia will be reviewed, in order to understand if
a common mechanism of action may support this dual therapeutic indication. The
dopaminergic antidepressant action of substituted benzamides such as sulpiride,
has been proposed, since the late 1970s, by several authors and extensively
explored in preclinical experiments by our group. In Italy the first marketing
authorization obtained for the new substituted benzamide amisulpride, was with
the sole indication of dysthymia and therefore a solid clinical experience
exists in the use of substituted benzamides in mild forms of depression, with
more than 1 000 000 patients being treated in the last 7 years. The proposed
mechanism of action of substituted benzamides implies a selective modulation of
the dopaminergic system in the mesocorticolimbic area, important for cognitive
processing of internal and external cues, related to survival. The selective
antagonism of dopamine D2-D3 receptors has been evoked to explain, in small to
moderate doses (ie 50-100 mg day(-1)), the antidepressant effect and, in
moderate to medium doses (100-400 mg day(-1)), the reported efficacy on negative
symptoms of schizophrenia. Thus, substituted benzamides could represent the
first class of atypical antipsychotics successfully employed for both depressive
states and schizophrenia. Interestingly, recent evidence in the literature
suggests that depressive episodes belonging to the bipolar spectrum are among
'alternative indications' of other atypical antipsychotics such as olanzapine
and risperidone.
Pekkone, E., J. Hirvonen, et al. (2002). "Memory-based comparison process not
attenuated by haloperidol: a combined MEG and EEG study." Neuroreport
13(1): 177-81.
Auditory P50 and N100 responses reflect preattentive processing, whereas
subsequent mismatch negativity (MMN) response indexes memory-based comparison
process. Divergent ERP responses have been found in schizophrenia and in
Parkinson's disease (PD), which have abnormalities in cerebral dopamine
activity. We used simultaneously magnetoencephalography and
electroencephalography to investigate, whether a single dose of haloperidol, a
dopamine D2-receptor antagonist, modulates preattentive auditory processing
using a randomized, double-blind, placebo-controlled crossover design. Our
results showed that haloperidol did not alter MMN to frequency and duration
changes, whereas the magnetic MMN to frequency change was significantly
accelerated.The amplitude and latency changes of the electric and magnetic P50
and N100 were insignificant. Our results indicate that memory-based sound
comparison and preceding cortical processing underlying stimulus detection are
not attenuated by haloperidol, whereas haloperidol appears to accelerate
preattentive sound comparison.
Pilowsky, L. S. and P. J. Ell (2002). "Clozapine and dopamine D(2) blockade."
Am J Psychiatry 159(2): 324-5.
Potkin, S. G., G. Alva, et al. (2002). "A PET study of the pathophysiology of
negative symptoms in schizophrenia. Positron emission tomography." Am J
Psychiatry 159(2): 227-37.
OBJECTIVE: Positron emission tomography (PET) was used to compare cerebral
metabolic patterns in schizophrenic subjects with predominantly negative
symptoms (alogia, affective flattening, avolition, and attentional impairment)
and in those with predominantly positive symptoms. METHOD: Fourteen right-handed
male subjects with DSM-IV schizophrenia were assigned to groups with
predominantly negative or predominantly positive symptoms on the basis of their
post-drug-washout scores on the Positive and Negative Syndrome Scale. The
patients were compared to seven age- and gender-matched normal volunteers. PET
scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous
Performance Task to measure absolute glucose metabolic rates. Statistical
parametric mapping was used to estimate the regional metabolic differences
between groups. RESULTS: The subjects with predominantly negative symptoms had
significant differences in glucose metabolic rates, compared to both the
subjects with predominantly positive symptoms and the normal subjects. Negative
symptom subjects had a lower glucose metabolic rate in the right hemisphere,
especially in the temporal and ventral prefrontal cortices, compared to the
other groups, and higher metabolic rates in the cerebellar cortex and in the
lower deep cerebellar nuclei. Negative symptom subscale scores were negatively
correlated with glucose metabolic rates for most of the brain areas that
differentiated subjects with predominantly negative symptoms from those with
predominantly positive symptoms. CONCLUSIONS: Schizophrenic subjects with
predominantly negative symptoms have greater metabolic abnormalities than
subjects with predominantly positive symptoms, particularly in frontal,
temporal, and cerebellar circuitry. These results are consistent with
abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine,
and cerebellar-thalamic-prefrontal circuits, which may underlie the negative
symptoms of schizophrenia.
Prasad, S., P. Semwal, et al. (2002). "Molecular genetics of schizophrenia:
past, present and future." J Biosci 27 Suppl 1: 35-52.
Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of
inheritance which is also governed by non-genetic factors. Candidate genes
identified on the basis of biochemical and pharmacological evidence are being
tested for linkage and association studies. Neurotransmitters, especially
dopamine and serotonin have been widely implicated in its etiology. Genome scan
of all human chromosomes with closely spaced polymorphic markers is being used
for linkage studies. The completion and availability of the first draft of Human
Genome Sequence has provided a treasure-trove that can be utilized to gain
insight into the so far inaccessible regions of the human genome. Significant
technological advances for identification of single nucleo-tide polymorphisms
(SNPs) and use of microarrays have further strengthened research methodologies
for genetic analysis of complex traits. In this review, we summarize the
evolution of schizophrenia genetics from the past to the present, current trends
and future direction of research.
Pugsley, T. A., Y. H. Shih, et al. (2002). "The discovery of PD 89211 and
related compounds: selective dopamine D4 receptor antagonists." Prog
Neuropsychopharmacol Biol Psychiatry 26(2): 219-26.
The dopamine (DA) D2 family of receptors consists of the D2, D3, and D4
receptors. The DA D4 receptor is of interest as a target for drugs to treat
schizophrenia based upon its high affinity for the atypical antipsychotic
clozapine and its localization to the limbic and cortical regions of the brain.
As part of a program to identify novel DA D4 receptor antagonists, a high-volume
screen using the Parke-Davis compound library was initiated. This led to the
discovery of PD 89211 (benzenemethanol,
2-chloro-4-[4-[(1H-benzimidazol-2-yl)methyl]-1-piperzinyl]) that displaced
[3H]spiperone binding to hD4.2 with an affinity (Ki) of 3.7 nM. PD 89211
exhibited high selectivity for the DA D4.2 receptor (> 800-fold) as compared to
other hDA receptor subtypes, rat brain serotonin, and adrenergic receptors. In
vitro, PD 89211 had D4 receptor antagonist activity reversing quinpirole-induced
[3H]thymidine uptake in CHOpro5 cells (IC50 = 2.1 nM). Limited
structure-activity relationship (SAR) studies indicated that compounds with a
4-chloro-, 4-methyl-, and 3-chloro- substituents on the phenyl ring retained
high affinity for D4 receptors, while those with a 4-methoxy- and no substituent
had less affinity. While all clinically effective antipsychotics increase DA
synthesis (DOPA accumulation) in rodents, PD 89211 did not increase DA synthesis
in the DA-enriched striatum, indicating no effect on DA turnover and low
propensity for exhibiting motor side effects. However, it did increase
catecholamine synthesis in rat hippocampus, as did clozapine. Moreover, PD 89211
selectivity increased catecholamine synthesis in the hippocampus of wild type
but not in mice lacking D4 receptors, suggesting that one function of D4
receptors may be to modulate DA/norepinephrine (NE) turnover in this brain area
known to possess D4 receptors. The discovery of compounds like PD 89211 provides
a tool to help in understanding the function of DA D4 receptors in the CNS.
Rosenkranz, J. A. and A. A. Grace (2002). "Cellular mechanisms of infralimbic
and prelimbic prefrontal cortical inhibition and dopaminergic modulation of
basolateral amygdala neurons in vivo." J Neurosci 22(1): 324-37.
The basolateral amygdala (BLA) is believed to be involved in schizophrenia,
depression, and other disorders that display affective components. The neuronal
activity of the BLA, and BLA-mediated affective behaviors, are driven by sensory
stimuli transmitted in part from sensory association cortical regions. These
same behaviors may be regulated by prefrontal cortical (PFC) inputs to the BLA.
However, it is unclear how two sets of glutamatergic inputs to the BLA can
impose opposing actions on BLA-mediated behaviors; specifically, it is unclear
how PFC inputs exert inhibitory actions over BLA projection neurons. Dopamine
(DA) receptor activation enhances BLA-mediated behaviors. Although we have
demonstrated that DA suppresses medial PFC inputs to the BLA and enhances
sensory cortical inputs, the precise cellular mechanisms for its actions are
unknown. In this study we use in vivo intracellular recordings to determine the
means by which glutamatergic inputs from the PFC inhibit BLA projection neurons,
contrast that with glutamatergic inputs from the association sensory cortex
(Te3) that drive BLA projection neurons, and examine the effects of DA receptor
activation on neuronal excitability, spontaneous postsynaptic potentials (PSPs),
and PFC-evoked PSPs. We found that PFC stimulation inhibits BLA projection
neurons by three mechanisms: chloride-mediated hyperpolarization, a persistent
decrease in neuronal input resistance, and shunting of PSPs; all effects are
possibly attributable to recruitment of inhibitory interneurons. DA receptor
activation enhanced neuronal input resistance by a postsynaptic mechanism (via
DA D2 receptors), suppressed spontaneously occurring and PFC-evoked PSPs (via DA
D1 receptors), and enhanced Te3-evoked PSPs.
Russig, H., C. A. Murphy, et al. (2002). "Clozapine and haloperidol reinstate
latent inhibition following its disruption during amphetamine withdrawal."
Neuropsychopharmacology 26(6): 765-77.
Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a
non-reinforced stimulus retards subsequent conditioning to that stimulus.
Deficits in LI may reflect an inability to ignore irrelevant stimuli and are
studied as a model of the cognitive/attentional abnormalities found in
schizophrenia. We recently determined that pretreatment with escalating doses of
the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5
mg/kg, over 6 days) disrupts LI in rats tested in a 2-way active avoidance
paradigm during withdrawal. In the present study, we evaluated the effects of
the atypical neuroleptic clozapine and the typical neuroleptic haloperidol on
the expression of LI on day 4 of AMPH withdrawal. Neuroleptic injections were
given either 45 min prior to each of two tone preexposure sessions and a
subsequent tone-shock avoidance test session, or only prior to the test session.
As expected, saline-injected control groups showed LI during the test session,
as reflected by significantly reduced avoidance in tone preexposed vs.
non-preexposed rats. In contrast, animals pretreated with escalating doses of
AMPH did not show LI, due to the improved avoidance of the preexposed animals.
Both haloperidol (0.03 mg/kg) and clozapine (5 mg/kg) largely reversed the
disruptive influence of AMPH on LI regardless of whether these drugs were
administered prior to both preexposure and test sessions or only prior to the
test session. These results provide pharmacological validation for an AMPH
withdrawal model of schizophrenic symptoms.
Sanci, V., S. Houle, et al. (2002). "No change in dopamine D1 receptor in vivo
binding in rats after sub-chronic haloperidol treatment." Can J Physiol
Pharmacol 80(1): 36-41.
A frequent side effect in the long-term treatment of schizophrenia with the
dopamine D2 antagonist haloperidol (HAL) is the appearance of tardive dyskinesia
or, in animals, of repetitive involuntary vacuous chewing movements (VCMs). In
rats, chronic HAL-induced or D1 receptor-stimulated VCMs are suppressed by D1
antagonists, suggesting that this behavioral supersensitivity is mediated by D1
receptors. The goal of this study was to investigate in vivo the possible
relationship between D1 receptor binding and D1-mediated behavioral
supersensitivity, after subchronic HAL treatments. D1 agonist R-SKF 82957 and
antagonist SCH 23390, both labeled with carbon-11, were used to assess in vivo
D1 receptor binding. Rats were treated with HAL (1.5 mg/kg, i.p.) or vehicle for
21 days, followed by a 4 day washout period. No significant difference was found
in the regional brain binding of either radioligand. D1 receptor-mediated
behaviors including VCMs, grooming, and rearing were measured in control or
HAL-treated rats. VCMs were significantly increased in HAL-treated rats,
suggesting D1 receptor stimulation and possibly receptor supersensitivity. This
study failed to link the purported D1 receptor-mediated behaviors with in vivo
receptor binding measures of R-[11C]SKF 82957 or [11C]SCH 23390 in rat brain
regions.
Sato, M. (2002). "[Basic and clinical studies on methampetamine-related
psychosis]." Seishin Shinkeigaku Zasshi 104(3): 179-90.
Sawa, A. and S. H. Snyder (2002). "Schizophrenia: diverse approaches to a
complex disease." Science 296(5568): 692-5.
Schizophrenia is a debilitating mental illness that affects 1% of the
population. Despite intensive study, its molecular etiology remains enigmatic.
Like many common diseases, schizophrenia is multifactorial in origin, with both
genetic and environmental contributions likely playing an important role in the
manifestation of symptoms. Recent advances based on pharmacological studies,
brain imaging analyses, and genetic research are now converging on tantalizing
leads that point to a central role for several neurotransmitters, including
dopamine, glutamate, and serotonin, that may interface with neurodevelopmental
defects reflecting disease-related genetic aberrations. Here, we provide a brief
overview of the parallel approaches being used to identify the molecular causes
of schizophrenia and discuss possible directions for future research.
Scott, L., M. S. Kruse, et al. (2002). "Selective up-regulation of dopamine D1
receptors in dendritic spines by NMDA receptor activation." Proc Natl Acad
Sci U S A 99(3): 1661-4.
Glutamate, by activating N-methyl-d-aspartate (NMDA) receptors, alters the
balance between dopamine D1 and D2 receptor signaling, but the mechanism
responsible for this effect has not been known. We report here, using
immunocytochemistry of primary cultures of rat neostriatal neurons, that
activation of NMDA receptors recruits D1 receptors from the interior of the cell
to the plasma membrane while having no effect on the distribution of D2
receptors. The D1 receptors were concentrated in spines as shown by
colocalization with phalloidin-labeled actin filaments. The effect of NMDA on D1
receptors was abolished by incubation of cells in calcium-free medium and was
mimicked by the calcium ionophore ionomycin. Recruitment of D1 receptors from
the interior of the cell to the membrane was confirmed by subcellular
fractionation. The recruited D1 receptors were functional as demonstrated by an
increase in dopamine-sensitive adenylyl cyclase activity in membranes derived
from cells that had been pretreated with NMDA. These results provide evidence
for regulated recruitment of a G protein-coupled receptor in neurons, provide a
cell biological basis for the effect of NMDA on dopamine signaling, and
reconcile the conflicting hyperdopaminergic and hypoglutamatergic hypotheses of
schizophrenia.
Seeman, P. (2002). "Atypical antipsychotics: mechanism of action." Can J
Psychiatry 47(1): 27-38.
BACKGROUND: Although the principal brain target that all antipsychotic drugs
attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by
attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by
binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics
given in dosages within the clinically effective range do not bring about these
adverse clinical effects. To understand how these drugs work, it is important to
examine the atypical antipsychotics' mechanism of action and how it differs from
that of the more typical drugs. METHOD: This review analyzes the affinities, the
occupancies, and the dissociation time-course of various antipsychotics at
dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube
and in live patients. RESULTS: Of the 31 antipsychotics examined, the older
traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine,
fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine
itself to the dopamine D2 receptor, with dissociation constants that are lower
than that for dopamine. The newer, atypical antipsychotics such as quetiapine,
remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all
bind more loosely than dopamine to the dopamine D2 receptor and have
dissociation constants higher than that for dopamine. These tight and loose
binding data agree with the rates of antipsychotic dissociation from the
human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine,
and raclopride all dissociate very slowly over a 30-minute time span, while
radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate
rapidly, in less than 60 seconds. These data also match clinical brain-imaging
findings that show haloperidol remaining constantly bound to D2 in humans
undergoing 2 positron emission tomography (PET) scans 24 hours apart.
Conversely, the occupation of D2 by clozapine or quetiapine has mostly
disappeared after 24 hours. CONCLUSION: Atypicals clinically help patients by
transiently occupying D2 receptors and then rapidly dissociating to allow normal
dopamine neurotransmission. This keeps prolactin levels normal, spares
cognition, and obviates EPS. One theory of atypicality is that the newer drugs
block 5-HT2A receptors at the same time as they block dopamine receptors and
that, somehow, this serotonin-dopamine balance confers atypicality. This,
however, is not borne out by the results. While 5-HT2A receptors are readily
blocked at low dosages of most atypical antipsychotic drugs (with the important
exceptions of remoxipride and amisulpride, neither of which is available for use
in Canada) the dosages at which this happens are below those needed to alleviate
psychosis. In fact, the antipsychotic threshold occupancy of D2 for
antipsychotic action remains at about 65% for both typical and atypical
antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not.
At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS
remains at about 80% for both typical and atypical antipsychotics, regardless of
the occupancy of 5-HT2A receptors. RELEVANCE: The "fast-off-D2" theory, on the
other hand, predicts which antipsychotic compounds will or will not produce EPS
and hyperprolactinemia and which compounds present a relatively low risk for
tardive dyskinesia. This theory also explains why L-dopa psychosis responds to
low atypical antipsychotic dosages, and it suggests various individualized
treatment strategies.
Segman, R. H. and B. Lerer (2002). "Age and the relationship of dopamine D3,
serotonin 2C and serotonin 2A receptor genes to abnormal involuntary movements
in chronic schizophrenia." Mol Psychiatry 7(2): 137-9.
Segman, R. H., U. Heresco-Levy, et al. (2002). "Interactive effect of cytochrome
P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal
involuntary movements in chronic schizophrenia." Biol Psychiatry 51(3):
261-3.
BACKGROUND: Tardive dyskinesia is a chronic adverse effect of anti psychotic
drugs, where association with a polymorphic site in the dopamine D3 receptor
gene has been previously reported. Cytochrome P 450 17alpha-hydroxylase activity
has been implicated with modulation of central dopamine release as well as
neuroprotection. We investigated the association of a T -->C variation in the
cytochrome P 450 17alpha-hydroxylase gene with tardive dyskinesia in patients
with chronic schizophrenia. METHODS: Cytochrome P 450 17 allele and genotype
frequencies were compared between matched schizophrenia patients with (n = 55)
or without tardive dyskinesia (n = 58). Interactive effects of cytochrome P 450
17alpha-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal
involuntary movements were examined. RESULTS: There was no difference in
cytochrome P 450 17alpha-hydroxylase genotype distribution between patients with
and without tardive dyskinesia; however, patients carrying the cytochrome P 450
17alpha-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest
orofacial (p <.04), distal (p <.05), and incapacitation (p <.04) scores on the
Abnormal Involuntary Movements Scale. CONCLUSIONS: Schizophrenia patients who
carry the dopamine D3gly allele and the cytochrome P 450 17alpha-hydroxylase
A2-A2 genotype may be more likely to develop abnormal orofoacial and distal
involuntary movements and to be incapacitated by these movements when
chronically exposed to classical antipsychotic drugs.
Shirazi-Southall, S., D. E. Rodriguez, et al. (2002). "Effects of typical and
atypical antipsychotics and receptor selective compounds on acetylcholine efflux
in the hippocampus of the rat." Neuropsychopharmacology 26(5):
583-94.
Some atypical antipsychotic drugs appear to improve cognitive function in
schizophrenia and since acetylcholine (ACh) is of importance in cognition, we
used in vivo microdialysis to examine the effects of antipsychotics administered
acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the
hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine
produced robust increases in ACh up to 1500% and 500%, respectively. The
neuroleptics haloperidol, thioridazine, and chlorpromazine, as well as the
atypical antipsychotics risperidone and ziprasidone produced modest increases in
ACh by about 50-100%. Since most atypical antipsychotics affect a variety of
monoaminergic receptors, we examined whether selective ligands for some of these
receptors affect hippocampal ACh. Antagonists for the 5-HT(2A) (MDL 100,907),
the 5-HT(2C) (SB 242,084), the 5-HT(6) (Ro 04-6790), the D(2) (raclopride)
receptors, and the alpha(1)-adrenoceptors (prazosin) modestly increased ACh by
about 50%. The 5-HT(1A) agonist R-(+)-8-OH-DPAT and the alpha(2)-adrenoceptor
antagonist yohimbine significantly increased ACh by about 100% and 50%,
respectively. Thus, olanzapine and clozapine increased ACh to a greater extent
than other tested antipsychotics, explaining perhaps their purported beneficial
effect in cognitive function in schizophrenia. It appears that selective
activity at each of the monoaminergic receptors studied is not the sole
mechanism underlying the olanzapine and clozapine induced increases in
hippocampal ACh.
Shuwairi, S. M., A. Cronin-Golomb, et al. (2002). "Color discrimination in
schizophrenia." Schizophr Res 55(1-2): 197-204.
Neuropsychiatric conditions that involve dopaminergic depletion have been
associated with color discrimination deficits along the blue-hue (tritan, or
short-wavelength-sensitive) axis. Because dopamine dysregulation may be a major
factor in schizophrenia, we investigated color vision in this disorder. The
performance of males with schizophrenia (SZ, n = 16) and normal male control
subjects (CS, n = 14) was evaluated on five measures of color discrimination. SZ
made more hue discrimination errors than CS, but no pattern emerged regarding a
hue-specific axis of deficit. Dosage of anti-psychotic medication was not
correlated with performance on hue discrimination. These results suggest that in
medicated patients with schizophrenia, the dopaminergic disturbance, which may
involve system hyperactivity, does not produce tritan-specific color deficits
that have been observed in disorders involving dopaminergic hypoactivity.
Siegel, S. J., K. I. Winey, et al. (2002). "Surgically implantable long-term
antipsychotic delivery systems for the treatment of schizophrenia."
Neuropsychopharmacology 26(6): 817-23.
Non-adherence with medication remains a major correctable cause for poor outcome
in schizophrenia. We describe a surgically implantable preparation of
haloperidol with the aim that patients will have superior outcomes with improved
medication adherence from implants. In contrast to depot formulations,
implantable pellets could last many months, providing symptomatic improvement
for periods of time never before possible. Additionally, in the event of
unacceptable side effects, implants could be removed, offering a degree of
reversibility not available with depot formulations. A surgically-implantable
formulation of haloperidol has been created using biodegradable polymers.
Implants have been characterized for in-vitro kinetics, as well as in-vivo
bioactivity in rodents. Haloperidol implants demonstrate steady release of drug
for 5 months. Animals treated with haloperidol implants display increased
striatal D2 receptor expression as well as increased apomorphine stimulated
locomotion. Surgically-implantable formulations are a viable approach to provide
long-term delivery of antipsychotic medications to patients with psychotic
disorders.
Smith, S., M. J. Wheeler, et al. (2002). "The effects of antipsychotic-induced
hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis." J Clin
Psychopharmacol 22(2): 109-14.
Hyperprolactinaemia is commonly induced by antipsychotic medications that have
dopamine-blockade as their main mechanism of action. The purpose of this study
was to assess the effect of antipsychotic-induced hyperprolactinaemia on
hypothalamic-pituitary-gonadal axis (HPG) function.HPG axis function was
assessed in 67 consecutive outpatients who were diagnosed with schizophrenia and
stabilized for a period of not less than 2 years on typical antipsychotic
medication, by means of clinical history, relevant questionnaires and
measurement of plasma prolactin, estradiol, progesterone, testosterone, LH, FSH,
sex hormone binding globulin, and TSH levels. Normative laboratory data were
used to assess whether hormone levels fell within the reference range for a
normal population.There was a significant correlation between dose of medication
and plasma prolactin levels for the total group (P<0.001). Prolactin levels were
significantly negatively associated with sex hormone levels in females (P<0.05).
Males taking antipsychotic medication had a mean prolactin level of 404.1m/IU
and mean gonadotrophin and sex hormone levels that fell within normal limits.The
results of this study indicate that neuroleptic-induced prolactin secretion is a
dose-related side effect and, in females, the level of hyperprolactinaemia is
correlated with the degree of suppression of the HPG axis. Women taking
long-term prolactin-raising antipsychotic medications are likely to be
hyperprolactinaemic and have an associated hypogonadal state. In males,
prolactin levels remain within normal limits, but at the upper end, with no
apparent disturbance of reproductive hormones.
Stevens, J. R. (2002). "Schizophrenia: reproductive hormones and the brain."
Am J Psychiatry 159(5): 713-9.
OBJECTIVE: Onset of schizophrenia occurs during the reproductive period in more
than 80% of those affected. The author reviews neuroendocrine and physiologic
events that occur in the basal forebrain at the initiation of and throughout the
reproductive period and proposes their possible relationship to the onset of
schizophrenia. METHOD: The neuroendocrine changes that occur in specific areas
of the anterior basal forebrain during the reproductive period are reviewed and
analyzed in relation to reported anatomic, molecular, and biochemical
pathologies of schizophrenia. RESULTS: The reproductive period is associated
with development of regular pulsatile release in the brain and bloodstream of
gonadotropic releasing hormones from the hypothalamus, luteinizing and follicle
stimulating hormones from the pituitary, and gonadal hormones from the ovaries
and testes. In addition to being concentrated in the hypothalamus, brain
receptors for gonadotropic and gonadal hormones are concentrated in specific
subcortical forebrain nuclei of the limbic system that project to the thalamus
and to cortical and subcortical structures that subserve perception, cognition,
and behavior. CONCLUSIONS: There is a flood of estrogen and testosterone to the
brain and body during puberty and throughout the reproductive period. To avoid
hyperexcitability and seizures, the surge of these excitatory hormones must be
counterbalanced by appropriate inhibitory factors. Excessive focal inhibition
may be induced by increased release of or increased receptors for one or more
inhibitory transmitters, e.g., dopamine, serotonin, and gamma-aminobutyric acid
in the anterior basal forebrain. Further investigation of the physiology and
pathology of this brain region, where abnormal electrical activity was recorded
from individuals with schizophrenia many years ago and where dopamine D(2) and
dopamine D(3) receptors targeted by the most effective antipsychotic agents are
maximally expressed, could lead to greater understanding of the critical
pathophysiology for development of schizophrenia.
Stip, E. (2002). "Happy birthday neuroleptics! 50 years later: la folie du
doute." Eur Psychiatry 17(3): 115-9.
Given that we are celebrating the 50th birthday of neuroleptics introduction in
psychiatry, the author proposes to take a look at certain results related to
therapeutic practice. After a brief chronological literature review of the
clinical practices and theoretical models that have controlled drug treatment of
schizophrenia, the author presents a critical review of four meta-analyses.
Since Delay, Deniker and Harl's initial report, the story of neuroleptics
comprises several periods. In 1963, the hyper-dopaminergic theory of psychoses
was proposed. Another period began with models mainly based on the
serotonin/dopamine relative blockade receptor hypothesis. More recently, a new
framework to understand the differential effect of antipsychotics is related to
the appropriate modulation (e.g., fast dissociation) of the D2 receptor alone.
The concept of atypicality has become a new vista for research and to market new
compounds. However, after 50 years of neuroleptic drugs, are we able to answer
the following simple questions: Are neuroleptics effective in treating
schizophrenia? Is there a difference between atypical and conventional
neuroleptics? How do the efficacy and safety of newer antipsychotic drugs
compare with those of clozapine? Actually, the answers yielded by these simple
questions by meta-analysis should elicit in us a good deal of humility. If we
wish to base psychiatry on evidence-based medicine, we run a genuine risk in
taking a closer look at what has long been considered fact. Each psychiatrist
must continue to be critical, sceptical, optimistic (not overoptimistic) and to
learn in order to integrate the positive aspects of our growing knowledge base.
Subramanian, N. and H. O. Kalkman (2002). "Receptor profile of P88-8991 and
P95-12113, metabolites of the novel antipsychotic iloperidone." Prog
Neuropsychopharmacol Biol Psychiatry 26(3): 553-60.
Iloperidone is a novel atypical antipsychotic compound currently under clinical
development for the treatment of psychotic disorders. In radioligand binding
studies, iloperidone binds with high affinity to serotonin (5-HT) 5-HT2A and
noradrenaline alpha1 and alpha2C receptors [Neuropsychopharmacology (2001) 25,
904-914]. The human metabolism of iloperidone generates two major metabolites,
P88-8991 and P95-12113. The aim of this study was to compare the receptor
affinity profile of P88-8991 and P95-12113 with that of the parent compound. The
receptor affinity profile of P88-8991 is comparable to that of iloperidone. This
metabolite binds to the following monoamine receptors (pKi values in nM):
serotonin 5-HT2A receptors (9.56), adrenergic alpha1 (8.08) and alpha2C (7.79)
receptors, and D2A receptors (7.80). Lower affinity is seen for other dopamine,
serotonin, alpha2-adrenergic and histamine H1 receptors. In contrast, P95-12113
shows affinity for 5-HT2A receptors (pKi 8.15; which is 60-fold lower than that
of iloperidone), adrenergic alpha1 (7.67), alpha2C (7.32) and alpha2B (7.08)
receptors. Given this affinity profile, and the observation that P95-12113 does
not readily cross the blood-brain barrier, it is unlikely that this metabolite
contributes to the therapeutic effect of iloperidone in patients with
schizophrenia. However, the comparable receptor binding profile of P88-8991
indicates that it is likely to contribute to the clinical profile of
iloperidone.
Suhara, T., Y. Okubo, et al. (2002). "Decreased dopamine D2 receptor binding in
the anterior cingulate cortex in schizophrenia." Arch Gen Psychiatry
59(1): 25-30.
BACKGROUND: The clinical efficacy of dopamine D2 receptor antagonism on the
psychotic symptoms of schizophrenia has been widely demonstrated. However, most
in vivo imaging studies have not been able to detect significant changes in
striatal D2 receptors in schizophrenia. On the other hand, a number of studies
have reported abnormalities in the cerebral cortex of schizophrenia. The aim of
this study was to examine the extrastriatal D2 receptors of patients with
schizophrenia. METHODS: Eleven drug-naive male patients with schizophrenia were
examined with positron emission tomography using carbon 11-labeled FLB 457.
Symptoms were assessed using the Brief Psychiatric Rating Scale. Eighteen
healthy controls were used for comparison. Region-of-interest analysis was
performed using the reference tissue method, and binding potential (BP) was used
for the index of dopamine D2 receptor binding. RESULTS: The BP value was
significantly lower, by about 12.5%, in the anterior cingulate cortex in
drug-naive patients with schizophrenia than in healthy controls. A significant
negative correlation was observed between BP in the anterior cingulate cortex
and the positive symptom score on Brief Psychiatric Rating Scale. CONCLUSIONS:
The lower BP values indicate fewer D2 receptors in the anterior cingulate cortex
in patients with schizophrenia. Alterations in D2 receptor function in the
extrastriatal region may underlie the positive symptoms of schizophrenia.
Suzuki, T., J. Ishigooka, et al. (2002). "Enhancement of delayed release of
dopamine in the amygdala induced by conditioned fear stress in
methamphetamine-sensitized rats." Eur J Pharmacol 435(1): 59-65.
Behavior during conditioned fear stress, a form of psychological stress, and the
release of dopamine in the amygdala were measured over time using
methamphetamine-sensitized rats, which are considered to be a model of
hypersensitivity and vulnerability to emotional stress associated with
stimulant-induced psychosis and schizophrenia. Dopamine release in the amygdala
showed a delayed increase following completion of freezing behavior induced by
conditioned fear stress regardless of the presence or absence of
methamphetamine-sensitization. Since methamphetamine treatment did not lower the
basal level of dopamine in the amygdala, under the conditions of this study,
methamphetamine was presumed not to show neurotoxicity. On the other hand, basal
dopamine levels after 15 h of repeated electric foot shock were about 40% lower
than those in the control group (p<0.0002). In addition, dopamine release
following conditioned fear stress in animals repeatedly treated with
methamphetamine increased significantly from 40 to 100 min after conditioned
fear stress while the duration of freezing behavior or latency of the appearance
of grooming were not different from those in the control group. The above
results suggested that delayed dopamine release in the amygdala is a phenomenon
strongly associated with the emotional context of conditioned fear stress, and
hypersensitivity and vulnerability to stress are at least partially involved
with the overreaction to stress.
Swerdlow, N. R., A. Eastvold, et al. (2002). "Dopamine agonist effects on
startle and sensorimotor gating in normal male subjects: time course studies."
Psychopharmacology (Berl) 161(2): 189-201.
RATIONALE: Prepulse inhibition (PPI) of startle is a measure of sensorimotor
gating that is deficient in schizophrenia and in rodents treated with dopamine
(DA) agonists. Reduced PPI is reported in normal humans treated with direct or
indirect DA agonists. To facilitate future studies, we assessed the time course
of DA agonist effects on PPI in humans, for both direct (bromocriptine: 1.25,
2.5 mg; pergolide: 0.025, 0.1 mg) and indirect DA agonists (amphetamine: 20 mg;
amantadine: 200 mg) ( n=6-10/dose). METHODS: Baseline (no drug) levels of
acoustic and tactile startle, as well as uni- and cross-modal PPI, were assessed
in 63 normal adult males. Seven to ten days later, subjects were tested in five
sessions over 3.5 h after ingestion of placebo or active drug in a double-blind
design. RESULTS: Expected drug effects were observed in both autonomic (for
example, increased heart rate and blood pressure with amphetamine), somatic (for
example, "queasiness" with direct DA agonists), and psychological measures (for
example, "happiness", less "drowsiness" with amphetamine). Drugs increased
(bromocriptine) or decreased (amantadine) startle magnitude, and caused either
no change or modest, time-dependent effects on PPI. Amantadine increased PPI
over the test session, a pattern not observed with other DA agonists or placebo.
No consistent effects on PPI were observed with either bromocriptine, pergolide,
or amphetamine. Drug effects on startle did not consistently correlate with
self-assessment measures. CONCLUSIONS: Despite evidence of "bioactivity", under
the specific experimental conditions of this study, neither direct nor indirect
DA agonists had robust effects on startle or PPI. In some cases (for example,
amantadine), a time course was identified that will facilitate future studies of
DA agonist effects on PPI in humans.
Tamminga, C. A. (2002). "Partial dopamine agonists in the treatment of
psychosis." J Neural Transm 109(3): 411-20.
The discovery and characterization of dopamine in the mammalian brain earned Dr.
Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about
dopamine pharmacology, came his proposal of the existence and critical role of
dopamine autoreceptors in the overall regulation of dopamine-mediated
neurotransmission. In this paper, the rationale, the putative mechanisms, and
pertinent clinical data are reviewed to support the idea of the clinical
relevance of dopamine agonists, especially partial agonists, in the treatment of
psychosis. Evidence was gathered for the usefulness of this strategy in
schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA).
But clinical relevance was not a reality before the application of (-)-3PPP.
These clinical results are presented. Moreover, now a partial dopamine agonist,
aripiprazole, has been developed and will likely be marketed by BMS and Otsuka
for the treatment of psychosis and will be the first drug in this class to be
commercially available. Partial dopamine agonists represent the next new class
of antipsychotic drugs, effective in treating schizophrenia.
Tripodianakis, J., M. Markianos, et al. (2002). "Biogenic amine turnover and
serum cholesterol in suicide attempt." Eur Arch Psychiatry Clin Neurosci
252(1): 38-43.
The investigation of biological correlates of suicidal behavior is important in
searching for possible changes in neuronal systems activity related to that
behavior, so that pharmacological interventions may be proposed, especially in
high-risk subjects. In a sample of 111 subjects admitted in a general hospital
after suicide attempt, we studied the turnover of neurotransmitters by measuring
the urinary output of the main metabolites of serotonin, dopamine and
noradrenaline (5-HIAA, HVA, MHPG respectively), as well as serum cholesterol,
and compared them to those of a group of 62 healthy controls. Venous blood
samples and urine samples were collected withi