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RESÚMENES JUNIO 2004 |
Psychotic Disorders &
Antipsychotics
Placebo-Controlled
Evaluation of Four Novel Compounds for the Treatment of Schizophrenia and
Schizoaffective Disorder
Herbert Y. Meltzer, Lisa
Arvanitis, Deborah Bauer, and Werner Rein, Meta-Trial Study Group
Am J Psychiatry
161:975-984, June 2004
OBJECTIVE: Four studies using identical protocols evaluated the
safety and efficacy of four novel, evidence-based targets for
antipsychotic agents: a neurokinin (NK3) antagonist (SR142801),
a serotonin 2A/2C (5-HT2A/2C) antagonist (SR46349B), a central
cannabinoid (CB1) antagonist (SR141716), and a neurotensin
(NTS1) antagonist (SR48692). METHOD: Adults with schizophrenia or
schizoaffective disorder (N=481) were randomly assigned in a 3:1:1
ratio to receive fixed doses of investigational drug, placebo, or
haloperidol for 6 weeks. Primary efficacy variables included changes
from baseline in total score on the Positive and Negative Syndrome
Scale, severity of illness score on the Clinical Global Impression (CGI),
and total score and psychosis cluster score on the Brief Psychiatric
Rating Scale (BPRS). RESULTS: Significantly greater improvement in
all primary efficacy variables was seen in the group receiving
haloperidol than in the group receiving placebo at 6 weeks (endpoint
analyses), indicating the validity of the study. The group receiving
the NK3 antagonist showed significantly greater
improvement over baseline than the group receiving placebo as
measured by Positive and Negative Syndrome Scale total score, CGI
severity of illness score, and BPRS psychosis cluster score. Reductions
in the Positive and Negative Syndrome Scale total and negative
scores in the group receiving the 5-HT2A/2C antagonist were
significantly larger than those in the group receiving placebo. The
improvements in psychopathology produced by the NK3 and
5-HT2A/2C antagonists were smaller than those produced by
haloperidol, although the response to the NK3 antagonist was
positively correlated with plasma levels. The groups receiving the
CB1 and NTS1 antagonists did not differ from the group
receiving placebo on any outcome measure. All investigational drugs
were well tolerated. CONCLUSIONS: The novel design used in this
study permitted the use of a smaller number of patients receiving
placebo to test the efficacy of the four novel compounds. The NK3
and 5-HT2A/2C antagonists showed evidence of efficacy in the
treatment of schizophrenia and schizoaffective disorder. Study
limitations preclude a definitive conclusion on the efficacy of CB1
and NTS1 antagonists in the treatment of schizophrenia. Further
study of these two promising nondopaminergic mechanisms to treat
schizophrenia and schizoaffective disorder appears indicated.
Comparative Effect of Atypical and Conventional Antipsychotic Drugs on Neurocognition in First-Episode Psychosis: A Randomized, Double-Blind Trial of Olanzapine Versus Low Doses of Haloperidol
Richard S.E. Keefe, Larry J. Seidman, Bruce K. Christensen,
Robert M. Hamer, Tonmoy Sharma, Margriet M. Sitskoorn, Richard R.J. Lewine,
Deborah A. Yurgelun-Todd, Ruben C. Gur, Mauricio Tohen, Gary D. Tollefson, Todd
M. Sanger, and Jeffrey A. Lieberman. HGDH Research Group
Am J Psychiatry 161:985-995, June 2004
OBJECTIVE: The
effect of antipsychotic medication on neurocognitive function
remains controversial, especially since most previous work has compared
the effects of novel antipsychotic medications with those of high
doses of conventional medications. This study compares the
neurocognitive effects of olanzapine and low doses of haloperidol in
patients with first-episode psychosis. METHOD: Patients with a first
episode of schizophrenia, schizoaffective disorder, or
schizophreniform disorder (N=167) were randomly assigned to
double-blind treatment with olanzapine (mean modal dose= 9.63
mg/day) or haloperidol (mean modal dose=4.60 mg/day) for the 12-week
acute phase of a 2-year study. The patients were assessed with a
battery of neurocognitive tests at baseline and 12 weeks after
beginning treatment. RESULTS: An unweighted neurocognitive composite
score, composed of measures of verbal fluency, motor functions,
working memory, verbal memory, and vigilance, improved significantly
with both haloperidol and olanzapine treatment (effect sizes of 0.20
and 0.36, respectively, no significant difference between groups). A
weighted composite score developed from a principal-component
analysis of the same measures improved to a significantly greater
degree with olanzapine, compared with haloperidol. Anticholinergic
use, extrapyramidal symptoms, and estimated IQ had little effect on
the statistical differentiation of the medications, although
duration of illness had a modest effect. The correlations of
cognitive improvement with changes in clinical characteristics and
with side effects of treatment were significant for patients who
received haloperidol but not for patients who received olanzapine.
CONCLUSIONS: Olanzapine has a beneficial effect on neurocognitive
function in patients with a first episode of psychosis. However, in
a comparison of the effects of olanzapine and low doses of
haloperidol, the difference in benefit is small.
Low
Dopamine D2 Receptor Binding in Subregions of the Thalamus in
Schizophrenia
Fumihiko Yasuno, Tetsuya Suhara, Yoshiro Okubo, Yasuhiko
Sudo, Makoto Inoue, Tetsuya Ichimiya, Akihiro Takano, Kazuhiko Nakayama,
Christer Halldin, and Lars Farde
Am J Psychiatry 161:1016-1022, June 2004
OBJECTIVE:
Several structural and functional brain imaging studies have pointed
to a disturbance of thalamic subnuclei in patients with
schizophrenia. The dopamine hypothesis of schizophrenia has,
however, not been thoroughly examined in terms of this complex
structure, which has connections with most brain regions of central
interest in schizophrenia research. The aim of the present study was
to examine dopamine D2 receptor binding in subregions of
the thalamus in patients with schizophrenia. METHOD: The authors
used positron emission tomography and the radioligand [11C]FLB457
to examine dopamine D2 receptor binding in thalamic subregions
of 10 drug-naive patients with schizophrenia. Binding potential was
calculated by the reference tissue method and used as an index for
dopamine D2 receptor binding. Comparisons were made with
19 healthy subjects. Subregions of interest were defined on
individual magnetic resonance images using a percentage-based operational
approach. Clinical symptoms were rated by using the Brief
Psychiatric Rating Scale (BPRS). RESULTS: The [11C]FLB457 binding
potential was lower in the central medial and posterior subregions
of the thalamus in patients with schizophrenia. At a functional level,
there was a significant negative correlation between binding
potential and BPRS positive symptom scores. CONCLUSIONS: The
subregions with low D2 receptor binding comprise primarily
the dorsomedial nucleus and pulvinar, two important components in
circuitries previously suggested in the pathophysiology of
schizophrenia. Aberrant dopaminergic neurotransmission in thalamic
subregions might be a mechanism underlying positive symptoms in
schizophrenia.
Cerebellar, Prefrontal Cortex, and Thalamic Volumes Over Two Time Points in Adolescent-Onset Schizophrenia
Anthony C. James, Susan James, David M. Smith, and Auxi
Javaloyes
Am J Psychiatry 161:1023-1029, June 2004
OBJECTIVE:
Structural and functional studies implicate multiple brain lesions
as a basis for a functional dysconnectivity underlying the cognitive
and symptom profiles in schizophrenia. The aim of this study was to
examine the hypothesis that early-onset schizophrenia is associated
with structural abnormalities in the prefrontal cortex, thalamus, and
cerebellum, compatible with a dysconnectivity syndrome. METHOD: Two
magnetic resonance imaging scans of 16 patients and 16 normal
comparison subjects were undertaken on average 2 to 3 years apart.
The participants were all from a defined geographic area in the
United Kingdom with a population of 2.5 million. RESULTS: In
comparison to the normal adolescents, the schizophrenic subjects
demonstrated low prefrontal cortex and thalamic volumes. The
relatively large difference in prefrontal and thalamic volumes in
these adolescents with schizophrenia implies a more severe disease
process than in adult subjects. CONCLUSIONS: The thalamic and
frontal lobe findings provide preliminary, supportive structural
evidence for a neurodevelopmental basis for a dysconnectivity
syndrome, although the cerebellar findings were inconclusive.
Prospective Study of Neurological Abnormalities in Offspring of Women With Psychosis: Birth to Adulthood
Erland W. Schubert, and Thomas F. McNeil
Am J Psychiatry 161:1030-1037, June 2004
OBJECTIVE: The
authors prospectively investigated neurological abnormalities in 75
young adult offspring of mothers with psychotic disorders and 91
offspring of comparison mothers with no psychosis history. They also
studied the stability of these abnormalities from birth to
adulthood. METHOD: Neurological abnormalities were previously
studied in infancy and at 6 years of age. In this study, they were
blindly assessed with a comprehensive neurological assessment scale
at a mean age of 22.4 years in a 93.3% effective follow-up of the
sample. RESULTS: In relation to the comparison subjects (N=88) and
offspring of mothers with affective psychosis (N=22), the adult
offspring of mothers with schizophrenia (N=28) had significantly
more neurological abnormalities. More soft signs, primitive
reflexes, involuntary movements, and cranial nerve abnormalities
characterized a subgroup (32%) among these offspring. The offspring
of mothers with affective psychosis were not different from
comparison subjects. The extension of schizophrenia and affective
psychosis risk groups to include additional maternal "spectrum
cases" (N=10 and N=14, respectively) generally yielded similar
results. Neurological abnormalities at 22 years were significantly
associated with neurological abnormalities at age 6, but not in
infancy, among the total high-risk group, offspring of mothers with
schizophrenia, and comparison offspring. CONCLUSIONS: High levels of
neurological abnormalities are found in a substantial proportion of
offspring of mothers with schizophrenia but not offspring of mothers
with affective psychosis. This suggests that familial risk for
schizophrenia is associated with neurodevelopmental disturbance that
is manifest throughout life and belongs to a different biological
continuum from that of affective psychosis.
Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia
Anna Maria Meaney, Shubulade Smith, O. D. Howes, Moira
O’brien, Robin M. Murray, Veronica O’keane
The British Journal of Psychiatry (2004)
184: 503-508
Background High
rates of osteoporosis in schizophrenia may result from the
prolactin-raising effects of some antipsychotic medication.
Aims To
examine bone mineral density in relation to relevant endocrine
variables in patients with schizophrenia taking prolactin-raising antipsychotics.
Method
Fifty-five patients who had been receiving prolactin-raising antipsychotic
medication for >10 years underwent dual-energy X-ray
absorptiometry of their lumbar and hip bones. Among the endocrine
variables assessed were plasma prolactin and sex hormones.
Results
Age-related reduced bone mineral density measures were found in 17
(57%) of the male and 8 (32%) of the female patients. Higher doses
of the female patients. Higher doses of medication were associated
with increased rates of both hyperprolactinaemia and bone mineral
density loss. Bone loss for the whole group was correlated with
medication dose, and for men was inversely correlated with
testosterone values.
Conclusions
These results suggest that patients with schizophrenia on long-term
prolactin-raising antipsychotic medication are at high risk of
developing reduced bone mineral density as a consequence of
hyperprolactinaemia-induced hypogonadism.
Clozapine maintenance therapy in schizophrenia.
Gaszner P,
Makkos Z.
Prog Neuropsychopharmacol Biol Psychiatry. 2004 May;28(3):465-9.
Long-term pharmacotherapy with antipsychotic agents is an important aspect of
the management of schizophrenia. In patients responsive to the chosen
treatment, maintenance therapy is usually conducted by halving the drug dose
that has proven effective during the acute phase. This strategy is suitable for
maintaining remission; moreover, it can improve the patients' quality of life.
Records from over 1000 patients treated with clozapine during the past 22 years
were examined; 782 of these patients were diagnosed with schizophrenia
according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth
Edition-Text Revision (DSM-IV-TR) criteria (with the modification in early
years). From this group, 181 patients were treated with clozapine for at least
a year. The mean duration of long-term maintenance treatment with clozapine was
12.2+/-4.25 years (range: from 14.5 months to 18 years). Clozapine was
administered in a daily dose of 50-200 mg (mean: 71.5+/-14.12 mg). In 76
schizophrenics, treatment was initiated with clozapine, whereas 105 patients
were switched over from other treatments after their failure. The control group
comprised 152 patients on long-term maintenance therapy with haloperidol.
Clozapine administered for long-term maintenance therapy was effective both in
paranoid and in catatonic schizophrenia. It also accomplished good results in
patients with disorganized or residual schizophrenia, as well as in individuals
with schizoaffective psychosis. Relapse rate was similar to that observed in
the haloperidol group; however, patient compliance, side-effect profile, and
therapeutic efficacy were all superior in the clozapine group. Long-term
maintenance therapy with clozapine is successful. Compliance is good;
schizophrenic patients are willing to take this atypical antipsychotic for
years on end. Clozapine treatment is associated with a low relapse rate and a
favorable safety profile.
Violence
in schizophrenia versus limbic psychotic trigger reaction: Prefrontal aspects
of volitional action
Anneliese
A. Pontius
Aggression and Violent Behavior .Volume 9, Issue 5 , August 2004, Pages
503-521
Two
basic kinds of violence in psychoses are juxtaposed: In schizophrenia violence
is mostly determined by a persisting distortion of the content of thought
through delusions and/or hallucinations, while the prefrontal mediation of
intentional volition of action behavior is largely intact. Conversely, all
prefrontal functions are briefly, but severely impaired by the fronto–limbic
imbalance proposed in a subtype of partial limbic seizures, limbic psychotic
trigger reaction (LPTR). LPTR is based on the animal model of limbic seizure
kindling (through intermittent mild stimuli) in primates, evoking nonconvulsive
"behavioral seizures" with indications of visual hallucinations.
Additional prefrontal factors contributing to violence both in schizophrenia
and most severely in LPTR, concern the inability to appropriately reset a plan
of ongoing action upon intervening circumstances, and/or a reduced ability for
the cognitive "appreciation" of the consequences and implications of
the acts.
Pyramidal
cell size reduction in schizophrenia: evidence for involvement of auditory
feedforward circuits
Robert
A. Sweet, Sarah E. Bergen, Zhuoxin Sun, Allan R. Sampson, Joseph N. Pierri and
David A. Lewis
Biological Psychiatry .Volume 55, Issue 12 , 15 June 2004, Pages
1128-1137
Background
Subjects
with schizophrenia have decreased gray matter volume of auditory cortex in
structural imaging studies and exhibit deficits in auditory sensory processing
that might reflect impairments of feedforward and/or feedback circuits within
the auditory cortex. Recently, we reported that one component of these
circuits, pyramidal cells in deep layer 3 of the auditory association cortex
(area 42), has reduced mean somal volume in subjects with schizophrenia. To
discriminate between involvement of feedforward and feedback circuit
components, we examined pyramidal cell somal volume in layer 3 of primary
auditory cortex (feedforward) and layer 5 of auditory association cortex
(feedback).
Methods
We
estimated somal volumes of pyramidal neurons in deep layer 3 of area 41 and
layer 5 of area 42 in subjects with schizophrenia (area 41, n = 16; area 42, n
= 18), each of whom was matched to one normal comparison subject for gender,
age, and postmortem interval.
Results
In deep
layer 3 of area 41, mean pyramidal cell somal volume was significantly reduced,
by 10.4%. No significant reduction was present in layer 5 of area 42.
Conclusions
Pyramidal
cell somal volume is reduced in layer 3 of area 41 and area 42, but not in
layer 5 of area 42, of subjects with schizophrenia. This pattern of
abnormalities is consistent with impairments of auditory feedforward projection
neurons.
Sanjiv
Kumra, Manzar Ashtari, Marjorie McMeniman, Joshua Vogel, Rachel Augustin, David
E. Becker, Emilie Nakayama, Kunsang Gyato, John M. Kane, Kelvin Lim and Philip
Szeszko
Biological Psychiatry .Volume 55, Issue 12 , 15 June 2004, Pages
1138-1145
Background
Research
suggests that brain frontal white matter (WM) might be qualitatively altered in
adolescents with early onset schizophrenia (EOS). Diffusion tensor imaging
provides a relatively new approach for quantifying possible connectivity of WM
in vivo.
Methods
Diffusion
tensor imaging was used to examine the WM integrity of frontal regions at seven
levels from 25 mm above to 5 mm below the anterior commissure–posterior
commissure (AC-PC) plane. Three other regions were examined: the occipital
region at the AC-PC plane and the genu and splenium of the corpus callosum.
Fractional anisotropy was compared between 12 adolescents (nine male, 3 female)
with EOS (onset of psychotic symptoms by age 18 years) and nine age-similar
healthy comparison subjects (six male, 3 female).
Results
Adolescents
with EOS had significantly reduced fractional anisotropy in the frontal WM at
the AC-PC plane in both hemispheres and in the occipital WM at the AC-PC plane
in the right hemisphere.
Conclusions
These
preliminary data support a hypothesis that alterations in brain WM integrity
occur in adolescents with EOS. Abnormalities found in this study were similar
to those reported in adults with chronic schizophrenia. Additional studies are
needed to assess whether there is progression of WM abnormalities in
schizophrenia.
Cerebellar
dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive,
and neuroanatomic correlates of cerebellar neurologic signs
Beng-Choon
Ho, Carmencita Mola and Nancy C. Andreasen
Biological Psychiatry .Volume 55, Issue 12 , 15 June 2004, Pages
1146-1153
Background
There is
increasing evidence that, aside from motor coordination, the cerebellum also
plays an important role in cognition and psychiatric disorders. Our previous
studies support the hypothesis that cerebellar dysfunction may disrupt the
cortico-cerebellar-thalamic-cortical circuit and, in turn, lead to cognitive
dysmetria in schizophrenia. The goal of this study was to investigate
cerebellar dysfunction in schizophrenia by examining the clinical, cognitive,
and neuroanatomic correlates of cerebellar neurologic signs in schizophrenia
patients.
Methods
We
compared the prevalence of cerebellar neurologic signs in 155 neuroleptic-naive
schizophrenia patients against 155 age- and gender-matched healthy control
subjects. Differences in clinical characteristics, standardized neuropsychologic
performance, and magnetic resonance imaging brain volumes between patients with
and without cerebellar signs were also examined.
Results
Patients
had significantly higher rates of cerebellar signs than control subjects, with
coordination of gait and stance being the most common abnormalities. Patients
with lifetime alcohol abuse or dependence were no more likely than those
without alcoholism to have cerebellar signs. Presence of cerebellar signs in
patients was associated with poorer premorbid adjustment, more severe negative
symptoms, poorer cognitive performance, and smaller cerebellar tissue volumes.
Conclusions
These
findings lend further support for cerebellar dysfunction in schizophrenia.
Potential noradrenergic targets for cognitive enhancement
in schizophrenia.
Friedman JI, Stewart DG,
Gorman JM.
CNS Spectrums
2004;9(5):350-356.
Substantial evidence suggests that alterations in
noradrenergic function contribute to the cognitive impairments of
schizophrenia. Activation of post-junctional alpha2a-adrenergic receptors in
the prefrontal cortex by the alpha2a-selective agonist guanfacine has
demonstrated some preliminary benefit in subjects with schizophrenia treated
with atypical antipsychotics. alpha1-adrenergic receptor activity may be less
important in mediating the cognitive impairments of schizophrenia.
beta-adrenergic receptors may serve as another potential target for cognitive
remediation in schizophrenia. However, the potential increase in memory
consolidation in schizophrenia patients produced by beta-adrenergic agonists
may be outweighed by the impairment in cognitive flexibility and executive
functioning produced by beta-adrenergic agonists. Finally, norepinephrine
reuptake inhibitors, such as atomoxetine, hold promise as potential cognitive
enhancers in schizophrenia because of their ability to indirectly but
selectively increase extracellular dopamine concentrations in the prefrontal
cortex.
Olanzapine plasma concentration, average daily
dose, and interaction with co-medication in schizophrenic patients.
Bergemann N, Frick A,
Parzer P, Kopitz J.
Pharmacopsychiatry
2004;37(2):63-68.
Background: Olanzapine, a thienobenzodiazepine, is
one of the relatively new atypical antipsychotic drugs. The lowest threshold of
effective olanzapine plasma levels in inpatient treatment is assumed to be 9
ng/ml [28]. Very little is known about the plasma concentration in patients at
various oral doses of olanzapine or about the clinically relevant interactions
with co-medications. Methods: In 71 schizophrenic patients (age 32.6 plus or
minus sign 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels
were assessed in 377 tests by high-performance liquid chromatography (HPLC)
with electrochemical detection. Fifty-six of these plasma levels were assessed
while patients were receiving olanzapine as monotherapy; otherwise, the plasma
levels were assessed with the patients receiving various co-medications.
Results: The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40
mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8
ng/ml, range 1.2-208 ng/ ml). The plasma concentration of olanzapine increased
linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance
analysis considering age and sex as covariables showed a significant difference
in the dose-corrected plasma levels of olanzapine among 40 smokers and 31
non-smokers; age and sex did not affect the dose-corrected plasma levels.
However, women received a significantly lower daily dose of olanzapine under
routine clinical study conditions. No differences could be detected among the
dose-corrected plasma concentration of those patients who were taken off
olanzapine because they did not respond (n = 14) or because of side effects (n =
5) and those who were discharged while still on olanzapine. Under the
co-medication with fluvoxamine, significantly higher dose-corrected olanzapine
plasma concentrations were found than with olanzapine monotherapy, whereas
significantly lower dose-corrected olanzapine plasma concentrations were
detected under lithium and trimipramine co-medication. Under co-medication with
amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the
dose-corrected olanzapine plasma concentrations were no different than the
plasma levels under olanzapine monotherapy. Conclusions: The relevance of
therapeutic drug monitoring is emphasized with respect to the data presented
and to the literature. Future studies should examine, in particular, the
effects of a wider range of co-medications in a larger patient sample.
Blood dyscrasias induced by psychotropic
drugs.
Stubner S, Grohmann R,
Engel R, et al.
Pharmacopsychiatry
2004;37 Suppl 1(-):S70-S78.
Drugs can cause a variety of blood dyscrasias, e.
g., by interfering with hematopoiesis in the bone marrow or damaging mature
blood cells by antibodies. Although numerous reports on the risks of adverse
hematological effects associated with psychotropic drugs have led to stringent
monitoring requirements for some compounds, particularly neuroleptics, it is
still difficult to estimate the true prevalence of such risks. Sixteen episodes
of thrombocytopenia, 63 of neutropenia, 22 of agranulocytosis, 4 episodes of
severe neutro- and thrombocytopenia, and 2 of pancytopenia were documented by
the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der
Psychiatrie) in a population of 122,562 patients between 1993 and 2000. All
cases were related to the epidemiological data provided for this population and
systematically analyzed as regards history of medication, co-medication, and
the clinical course. Putative risk rates for the main groups of medications and
a number of drugs could be estimated with this database. Most changes in the
white blood cell counts, which were rated as probably or definitely
drug-induced, were attributed to clozapine (0.18 % of patients exposed),
carbamazepine (0.14 %) and perazine (0.09 %). In patients on newer atypical
neuroleptics, we documented neutropenia assumed to be probably or definitely
drug-related in five patients during treatment with olanzapine and in one case
with risperidone. In all five olanzapine-related cases, the drugs were the sole
cause of the adverse drug reactions. All surveyed patients who received
clozapine showed no difference in age and gender distribution from those who
developed hematological changes. Incidences of hematological changes for
antidepressants were much lower (about 0.01 %). Although the methodological
accuracy of these findings has to be critically discussed these data could be
of considerable clinical relevance and should be helpful in making clinical
treatment decisions.
Targeting
the dopamine D1 receptor in schizophrenia: insights for cognitive
dysfunction
Patricia S. Goldman-Rakic,
Stacy A. Castner, Torgny H. Svensson,
Larry J. Siever and Graham V. Williams
Background and
rationale Reinstatement of the function of working
memory, the cardinal cognitive process essential for human reasoning and
judgment, is potentially the most intractable problem for the treatment of
schizophrenia. Since deficits in working memory are associated with dopamine
dysregulation and altered D1 receptor signaling within prefrontal
cortex, we present the case for targeting novel drug therapies towards
enhancing prefrontal D1 stimulation for the amelioration of the
debilitating cognitive deficits in schizophrenia.
Objectives This
review examines the role of dopamine in regulating cellular and circuit
function within prefrontal cortex in order to understand the significance of
the dopamine dysregulation found in schizophrenia and related non-human primate
models. By revealing the associations among prefrontal neuronal function,
dopamine and D1 signaling, and cognition, we seek to pinpoint the
mechanisms by which dopamine modulates working memory processes and how these
mechanisms may be exploited to improve cognitive function.
Results and
conclusions Dopamine deficiency within dorsolateral
prefrontal cortex leads to abnormal recruitment of this region by cognitive
tasks. Both preclinical and clinical studies have demonstrated a direct
relationship between prefrontal dopamine function and the integrity of working
memory, suggesting that insufficient D1 receptor signaling in this
region results in cognitive deficits. Moreover, working memory deficits can be
ameliorated by treatments that augment D1 receptor stimulation,
indicating that this target presents a unique opportunity for the restoration
of cognitive function in schizophrenia.
Serotonin
receptors represent highly favorable molecular targets for cognitive
enhancement in schizophrenia and other disorders
Bryan L. Roth1,
2 
,
S. Mohammad Hanizavareh1 and Andrew E. Blum1
Rationale Current
treatments for schizophrenia adequately treat the positive symptoms of
schizophrenia but only modestly improve cognitive deficits. This review
provides evidence for and against the use of selective 5-HT receptor drugs as
cognition enhancing agents for schizophrenia and other disorders.
Methods Pre-clinical
and clinical literature concerned with the role of the serotonergic system in
cognition and memory as it relates to schizophrenia is reviewed. Individual
5-HT receptor subtypes for which selective drugs are available that are likely
to improve cognition are reviewed. Recommendations for clinical testing are
proposed.
Results and
conclusions Four 5-HT receptor systems (5-HT1A,
5-HT2A, 5-HT4, 5-HT6) are highlighted as
suitable targets for enhancing cognition and memory. Because many clinically
available antipsychotic drugs already target 5-HT1A, 5-HT2A
and 5-HT6 receptors, design of clinical trials will need to take
into account the serotonergic pharmacology of concurrently administered antipsychotic
medications. 5-HT1A partial agonists and 5-HT2A
antagonists have shown modest effectiveness in improving cognition in
schizophrenia. 5-HT6-selective compounds for cognition enhancement
are in late-stage clinical trials, while 5-HT4 compounds have not
yet been tested in humans for cognition enhancement.
Recommendations For
stand-alone therapy for enhancing cognition, 5-HT1A partial
agonists, 5-HT2A antagonists, 5-HT4 partial agonists and
5-HT6 antagonists are all likely to induce at least modest improvement
in cognition in schizophrenia. If 
add-on
therapy
is contemplated, antipsychotic drugs with weak affinities for serotonin
receptors should be used to avoid confounds. It is likely that serotonergic
drugs will soon be available as cognition enhancing medications for disorders
other than schizophrenia (e.g. dementia).
Adrenergic
targets for the treatment of cognitive deficits in schizophrenia
Amy F. T. Arnsten
Psychopharmacology 2004; Volume 174, Number
1: 25 - 31
Rationale The
cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in
schizophrenic patients. Although dopamine has been the major focus of
schizophrenia research, norepinephrine (NE) also has marked influences on PFC
cognitive functioning.
Objective This
review aims to identify the adrenergic receptors which may be appropriate
targets for therapeutic actions in schizophrenia.
Methods Studies
of adrenergic mechanisms influencing PFC function in animals and humans were
reviewed.
Results Modest
levels of NE engage postsynaptic 
2A-adrenergic
receptors and strengthen working memory. These beneficial effects have been
observed at both the behavioral and cellular levels in animals, and have
translated to the clinic in patients with PFC impairments. Thus, the 2A-adrenergic
receptor is a proven molecular target. In contrast, high levels of NE released
during stress impair PFC cognitive function via activation of protein kinase C
intracellular signaling, a pathway increasingly associated with the etiology of
schizophrenia. Blockade of 1
adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive
function in animals, and may have similar therapeutic actions in humans.
Blockade of the 2C
receptor may also be helpful in enhancing catecholamine release while blocking
detrimental DA actions in striatum.
Conclusion Highly selective
adrenergic agents may be useful for enhancing PFC function in schizophrenic
patients
The
NMDA receptor glycine modulatory site: a therapeutic target for improving
cognition and reducing negative symptoms in schizophrenia
Joseph T. Coyle
and Guochuan Tsai
Numerous clinical studies demonstrate that subanaesthetic doses
of dissociative anaesthetics, which are non-competitive antagonists at the NMDA
receptor, replicate in normal subjects the cognitive impairments, negative
symptoms and brain functional abnormalities of schizophrenia. Post-mortem and
genetic studies have identified several abnormalities associated with
schizophrenia that would interfere with the activation of the glycine modulatory
site on the NMDA receptor. Placebo controlled clinical trials with agents that
directly or indirectly activate the glycine modulatory site consistently reduce
negative symptoms and frequently improve cognition in patients with chronic
schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there
is convincing evidence that the glycine modulatory site on the NMDA receptor is
a valid therapeutic target for improving cognition and associated negative
symptoms in schizophrenia.
Targeting
metabotropic glutamate receptors for treatment of the cognitive symptoms of
schizophrenia
Bita Moghaddam
Psychopharmacology 2004; Volume 174, Number
1: 39 - 44
Several lines of evidence implicate NMDA receptor dysfunction
in the cognitive deficits of schizophrenia, suggesting that pharmacological
manipulation of the NMDA receptor may be a feasible therapeutic strategy for
treatment of these symptoms. Although direct manipulation of regulatory sites
on the NMDA receptor is the most obvious approach for pharmacological
intervention, targeting the G-protein coupled metabotropic glutamate (mGlu)
receptors may be a more practical strategy for long-term regulation of abnormal
glutamate neurotransmission. Heterogeneous distribution, both at structural and
synaptic levels, of at least eight subtypes of mGlu receptors suggests that
selective pharmacological manipulation of these receptors may modulate
glutamatergic neurotransmission in a regionally and functionally distinct
manner. Two promising targets for improving cognitive functions are mGlu5 or
mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal
transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate
that activation of these subtypes of mGlu receptors may be an effective strategy
for reversing cognitive deficits resulting form reduced NMDA receptor mediated
neurotransmission.
Cholinergic
targets for cognitive enhancement in schizophrenia: focus on cholinesterase
inhibitors and muscarinic agonists
Joseph I. Friedman
Psychopharmacology 2004; Volume 174, Number
1: 45 - 53
Rationale Alterations
in the central cholinergic system of patients with schizophrenia such as
reduced numbers of muscarinic and nicotinic receptors in the cortex and
hippocampus may contribute to the cognitive impairment of schizophrenia.
Therefore, pharmacological treatments that enhance central cholinergic function
may be useful as cognitive enhancers in schizophrenia.
Methods Searches
were conducted for articles which investigated alterations of central
cholinergic systems in patients with schizophrenia. Additional searches were
conducted for animal and human trials of potential cognitive enhancing
compounds that target the cholinergic system and any preliminary trials
conducted with schizophrenic patients.
Results Currently
available treatments which are potentially suitable for this purpose include
acetylcholinesterase inhibitors, muscarinic agonists, nicotinic agonists, and
allosteric potentiators of nicotinic receptor function. Although some open label
studies demonstrate modest cognitive improvements of schizophrenic patients
treated with donepezil, data from a blinded, placebo controlled study
demonstrate no effect. Data from a controlled trial of galantamine, a combined
acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic
receptor, indicates that this may be an effective alternative. In addition,
some preclinical data indicates that selective M1 muscarinic
agonists under development may have potential as cognitive enhancers and
antipsychotic treatments for schizophrenic patients.
Conclusions A
cholinergic approach to ameliorating the cognitive dysfunction of schizophrenia
appears viable. There is some preliminary data to support the efficacy of
combined acetylcholinesterase inhibitors and allosteric potentiators of the
nicotinic receptor, whereas future trials are awaited for more specific
muscarinic agonists currently under development.
Alpha-7
nicotinic receptor agonists: potential new candidates for the treatment of
schizophrenia
Laura F. Martin,
William R. Kem and Robert Freedman
Psychopharmacology 2004; Volume 174, Number
1: 54 - 64
Rationale and
objective Auditory sensory gating, a biological
measurement of the ability to suppress the evoked response to the second of two
auditory stimuli, is diminished in people with schizophrenia. Deficits in
sensory gating are associated with attentional impairment, and may contribute
to cognitive symptoms and perceptual disturbances. This inhibitory process,
which involves the alpha7 nicotinic receptor mediated release of
gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a
potential new target for therapeutic intervention in schizophrenia.
Method This
paper will review several lines of evidence implicating the nicotinic-cholinergic,
and specifically, the alpha7 nicotinic receptor system in the
pathology of schizophrenia and the evidence that alpha7 nicotinic
receptor agonists may ameliorate some of these deficits.
Results Impaired
auditory sensory gating has been linked to the alpha7 nicotinic
receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of
the promoter region of this gene are more frequent in people with
schizophrenia. Although nicotine can acutely reverse diminished auditory sensory
gating in people with schizophrenia, this effect is lost on a chronic basis due
to receptor desensitization. Clozapine is able to reverse auditory sensory
gating impairment, probably through an alpha7 nicotinic receptor
mechanism, in both humans and animal models with repeated dosing. The alpha7
nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also
enhance auditory sensory gating in animal models. DMXBA is well tolerated in
humans and improves several cognitive measures.
Conclusion Alpha-7
nicotinic receptor agonists appear to be reasonable candidates for the
treatment of cognitive and perceptual disturbances in schizophrenia.
Psychopharmacological
approaches to modulating attention in the five-choice serial reaction time
task: implications for schizophrenia
Y. Chudasama
and T. W. Robbins
Psychopharmacology 2004;Volume 174, Number
1: 86 - 98
Rationale In
schizophrenia, attentional disturbance is a core feature which may not only
accompany the disorder, but may precede the onset of psychiatric symptoms.
Objectives The
five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial
attention that has been used extensively in rats for measuring the effects of
systemic and central neurochemical manipulations on various aspects of
attentional performance, including selective attention, vigilance and executive
control. These findings are relevant to our understanding of the neural systems
that may be compromised in patients with schizophrenia.
Methods The
5CSRTT is conducted in an operant chamber that has multiple response locations,
in which brief visual stimuli can be presented randomly. Performance is
maintained using food reinforcers to criterion levels of accuracy. Various
aspects of performance are measured, including attentional accuracy and
premature responding, especially under different attentional challenges.
Results The
effects of systemic and intra-cerebral infusions of selective dopamine,
serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view
to identifying attention-enhancing effects that may be relevant to the
treatment of cognitive deficits in schizophrenia. In addition, some novel
agents such as modafinil and histamine receptor agents are also considered.
Examining the effects of selective neurochemical lesions helped define the
neural locus of attentional effects. Similarly, findings from microdialysis
studies helped identify the extracellular changes in neurotransmitters and
their metabolites in freely moving rats during performance of the 5CSRTT.
Conclusions The
monoaminergic and cholinergic systems have independent but complementary roles
in attentional function, as measured by the 5CSRTT. These functions are
predominantly under the control of the prefrontal cortex and striatum. These
conclusions are considered in the context of their application towards
therapeutic approaches for attentional disturbances that are typically observed
in schizophrenic patients.
Selective
alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a
novel target for the treatment of working memory dysfunction
David A. Lewis,
David W. Volk and Takanori Hashimoto
Psychopharmacology 2004; Volume 174, Number
1: 143 - 150
Rationale Disturbances
in critical cognitive processes, such as working memory, are now regarded as
core features of schizophrenia, but available pharmacological treatments
produce little or no improvement in these cognitive deficits. Although other
explanations are possible, these cognitive deficits appear to reflect a disturbance
in executive control, the processes that facilitate complex information
processing and behavior and that include context representation and
maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC).
Studies in non-human primates indicate that normal working memory function
depends upon appropriate GABA neurotransmission in the DLPFC, and alterations
in markers of GABA neurotransmission are well documented in the DLPFC of
subjects with schizophrenia.
Objectives Thus,
the purpose of this paper is to review the nature of the altered GABA
neurotransmission in the DLPFC in schizophrenia, and to consider how these
findings might inform the search for new treatments for cognitive dysfunction
in this illness.
Results and
conclusions Postmortem studies suggest that markers of
reduced GABA neurotransmission in schizophrenia may be selective for, or at
least particularly prominent in, the subclass of GABA neurons, chandelier
cells, that provide inhibitory input to the axon initial segment of populations
of pyramidal neurons. Given the critical role that chandelier cells play in
synchronizing the activity of pyramidal neurons, the pharmacological
amelioration of this deficit may be particularly effective in normalizing the
neural network activity required for working memory function. Because GABAA
receptors containing the a2 subunit are selectively localized to the
axon initial segment of pyramidal cells, and appear to be markedly up-regulated
in schizophrenia, treatment with novel benzodiazepine-like agents with
selective activity at GABAA receptors containing the a2
subunit may be effective adjuvant agents for improving working memory function
in schizophrenia.
The
hippocampus in schizophrenia: a review of the neuropathological evidence and
its pathophysiological implications
Paul J. Harrison
Psychopharmacology 2004; Volume 174, Number
1: 151 - 162
This paper puts the case for the hippocampus as being central
to the neuropathology and pathophysiology of schizophrenia. The evidence comes from
a range of approaches, both in vivo (neuropsychology, structural and functional
imaging) and post mortem (histology, morphometry, gene expression, and
neurochemistry). Neuropathologically, the main positive findings concern
neuronal morphology, organisation, and presynaptic and dendritic parameters.
The results are together suggestive of an altered synaptic circuitry or wiring
within the hippocampus and its extrinsic connections, especially with the
prefrontal cortex. These changes plausibly represent the anatomical component
of the aberrant functional connectivity that underlies schizophrenia.
Glutamatergic pathways are prominently but not exclusively affected. Changes
appear somewhat greater in the left hippocampus than the right, and CA1 is
relatively uninvolved compared to other subfields. Hippocampal pathology in
schizophrenia may be due to genetic factors, aberrant neurodevelopment, and/or
abnormal neural plasticity; it is not due to any recognised neurodegenerative
process. Hippocampal involvement is likely to be associated with the
neuropsychological impairments of schizophrenia rather than with its psychotic
symptoms.
Comparison
of characteristics between geriatric and younger subjects with schizophrenia in
community
Mao-Sheng
Ran, Meng-Ze Xiang, Yeates Conwell, J. Steven Lamberti, Ming-Sheng Huang,
You-He Shan and Xian-Zhang Hu
Journal of Psychiatric Research .Volume 38, Issue 4 , July-August 2004,
Pages 417-424
Relatively
little is known about the different characteristics of non-institutionalized
geriatric and younger subjects with schizophrenia. This study compared
demographic and clinical characteristics of all the geriatric, middle-age and
young subjects with schizophrenia living in a Chinese rural community.
Geriatric (age 
65
years) (N=51), middle-age (age 41–64 years) (N=263) and young subjects with
schizophrenia (age 15–40 years) (N=196) in a rural community were assessed with
the Present State Examination and Social Disability Screening Schedule. Age at
first onset was significantly older in geriatric male and female groups. While
there were no significant differences of negative symptoms among the three
groups, the rates of lifetime nuclear syndrome were significantly lower in
geriatric subjects compared to the other two groups. Geriatric subjects were
less likely to have been hospitalized (9.8%) than middle-age (19.0%) and
younger subjects (24.8%). Although the duration of illness was significantly
longer in geriatric subjects than in the other two groups, the clinical outcome
was significantly better in the geriatric group and social functioning scores
were similar among the three groups. Geriatric subjects were more likely to be
female, with longer duration of illness, fewer "core" symptoms,
relatively stable social functioning and clinical outcome. The pathogenesis and
psychopathology of geriatric subjects may be different compared to younger
subjects with schizophrenia.
Patients
with schizophrenia previously stabilized on conventional depot antipsychotics
experience significant clinical improvements following treatment with
long-acting risperidone
Robert
A. Lasser, Cynthia A. Bossie, Georges M. Gharabawi and Martin Turner
European Psychiatry .Volume 19, Issue 4 , June 2004, Pages
219-225
Background. – Conventional depot antipsychotics can
provide constant pharmacologic treatment, eliminating partial compliance and
reducing relapse risk. Atypical antipsychotics, have improved clinical profiles
but require daily dosing, compromising their overall effectiveness. As oral
risperidone provides safety and efficacy benefits over oral haloperidol,
improvements may be realized by replacing conventional with atypical agents in
long-acting therapy. This report examines 50-weeks of long-acting risperidone
therapy in patients previously stabilized with conventional depot
antipsychotics.
Methods. – A multi-center, open-label study enrolled
725 patients with schizophrenia or schizoaffective disorder, judged
clinically stable and maintained on stable antipsychotic doses
for ≥4 weeks. Assignment by clinician judgment to receive
25–75 mg of long-acting risperidone every 2 weeks for 50 weeks
followed, with performance of standard safety and efficacy assessments. Data
are presented on patients receiving conventional depot antipsychotic
monotherapy at study entry.
Results. – In the 188 (25.9%) patients receiving
conventional depot antipsychotic monotherapy at entry, mild-to-moderate mean
(±S.D.) Positive and Negative Syndrome Scale (PANSS)-total scores improved
significantly after receiving long-acting risperidone
(64.2 ± 18.9 to 58.2 ± 20.3; P < 0.001).
Clinical improvement of ≥20%, 40%, or 60% reduction in PANSS-total
score, occurred in 52%, 34%, and 16% of patients, respectively. ESRS subjective
ratings and objective physician ratings (Parkinsonism) decreased significantly
(P < 0.001).
Conclusion. – Stable patients with mild, residual
symptomatology treated with conventional depot antipsychotics experienced
significant improvement in psychiatric and movement disorder symptomatology
following 1-year of treatment with long-acting risperidone.
The deficit syndrome of the psychotic illness. A
clinical and nosological study
Victor Peralta1
and Manuel J. Cuesta1
European Archives of Psychiatry and Clinical
Neuroscience 2004;Volume 254, Number 3: 165 - 171
The deficit syndrome is thought to be specific to
and a subtype of schizophrenia; however, there are scarce or no data on the
prevalence and characteristics of this syndrome in non-schizophrenic psychoses.
The aim of this study was to explore the prevalence and correlates of different
types of negative symptoms (NegS) in a mixed sample of psychotic disorders.
Six-hundred and sixty psychotic inpatients were classified according to the
presence and type of NegS into the following groups: no NegS, transitory NegS,
persistent secondary NeS, persistent doubtful secondary NegS, and persistent
primary NegS (i. e., deficit symptoms). Furthermore, the nosological status of
this symptom classification such as its clinical and etiological correlates
were examined. Depending on the diagnostic criteria used for diagnosing schizophrenia,
the prevalence of the deficit syndrome in schizophrenia and in
non-schizophrenic psychoses ranged from 14%–32% and 2%–22%, respectively.
Deficit syndromes in both schizophrenic and non-schizophrenic patients shared
most of the syndrome-related clinical features. Regarding the associated
clinical pattern, the transitory NegS group was closer to the group without
NegS than to the groups with enduring NegS. Patient groups with enduring
primary and enduring secondary NegS did not show relevant clinical or
etiological differences, thus, suggesting that the primary versus secondary
issue may be less relevant than previously acknowledged. The deficit syndrome
may be diagnosed irrespective of the specific categories of psychotic
disorders.
Modafinil Improves Cognition and Attentional
Set Shifting in Patients with Chronic Schizophrenia
Danielle C Turner, Luke Clark,
Edith Pomarol-Clotet, Peter McKenna, Trevor W Robbins and Barbara J Sahakian
Neuropsychopharmacology
(2004) 29, 1363-1373
Modafinil,
a novel cognitive enhancer, selectively improves neuropsychological task
performance in healthy volunteers and adult patients with attention deficit
hyperactivity disorder (ADHD). It has been argued that persistent cognitive
deficits in patients with schizophrenia are responsible for the failure of many
patients to rehabilitate socially even when psychotic symptoms are in
remission. The present study examined the potential of modafinil as a cognitive
enhancer in schizophrenia. Twenty chronic patients with a diagnosis of
schizophrenia were entered into a double-blind, randomized, placebo-controlled
crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive
enhancing properties in schizophrenia similar to those observed in healthy
adults and adult patients with ADHD. Improvement was seen on short-term verbal
memory span, with trends towards improved visual memory and spatial planning.
This was accompanied by slowed response latency on the spatial planning task.
No effect on stop-signal performance was seen. Importantly, significant
improvement in attentional set shifting was seen, despite no effect of
modafinil on this task being seen in healthy volunteers or ADHD patients.
Modafinil may have potential as an important therapy for cognitive impairment
in patients with schizophrenia, particularly because of its beneficial effects
on attentional set shifting.
Effects of Nicotine on Cognitive Deficits in
Schizophrenia
Josette G Harris, Susan Kongs,
Diana Allensworth, Laura Martin, Jason Tregellas, Bernadette Sullivan, Gary
Zerbe and Robert Freedman
Neuropsychopharmacology
(2004) 29, 1378-1985
Several
lines of evidence suggest a pathophysiological role for nicotinic receptors in
schizophrenia. Activation by nicotine alters physiological dysfunctions, such
as eye movement and sensory gating abnormalities, but effects on
neuropsychological performance are just beginning to be investigated.
Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic
receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and
10 nonsmokers were assessed following the administration of nicotine gum and
placebo gum. The Repeatable Battery for the Assessment of Neuropsychological
Status was administered. Nicotine affected only the Attention Index; there were
no effects on learning and memory, language, or visuospatial/constructional
abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent
smokers after nicotine administration. The effects of nicotine in schizophrenia
do not extend to all areas of cognition. Effects on attention may be severely
limited by tachyphylaxis, such that decremented performance occurs in smokers,
while modest effects may be achieved in nonsmokers.
The differential effects of steady-state
fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy
volunteers.
Wang CY, Zhang
ZJ, Li WB, Zhai YM, Cai ZJ, Weng YZ, Zhu RH, Zhao JP, Zhou HH.
J Clin Pharmacol. 2004 Jul;44(7):785-92.
The combination of atypical antipsychotics and selective serotonin reuptake
inhibitors is an effective strategy in the treatment of certain psychiatric
disorders. However, pharmacokinetic interactions between the two classes of
drugs remain to be explored. The present study was designed to determine
whether there were different effects of steady-state fluvoxamine on the
pharmacokinetics of a single dose of olanzapine and clozapine in healthy male
volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9)
was administered orally. Following a drug washout of at least 4 weeks, all
subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of
10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of
olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time
points after the antipsychotics were given alone and when added to fluvoxamine.
No bioequivalence was found in olanzapine alone and cotreatment with
fluvoxamine for the mean peak plasma concentration (C(max)), the area under the
concentration-time curve from time 0 to last sampling time point (AUC(0-t)),
and from time 0 to infinity (AUC(0- infinity )). Under the cotreatment, C(max)
of olanzapine was significantly elevated by 49%, with a 32% reduced time
(t(max)) to C(max), whereas the C(max) and t(max) of clozapine were unaltered.
The cotreatment increased the AUC(0-t) and AUC(0- infinity ) of olanzapine by
68% and 76%, respectively, greater than those of clozapine (40% and 41%). The
presence of fluvoxamine also prolonged the elimination half-life (t(1/2)) of
olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced
the total body clearance (CL/F) of clozapine (78%) more significantly than it
did for olanzapine (42%). The apparent volume of distribution (V(d)) was
suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in
the clozapine regimen. A significant reduction in the N-desmethylclozapine to
clozapine ratio was present in the clozapine with fluvoxamine regimen. The
effects of fluvoxamine on different aspects of pharmacokinetics of the two
antipsychotics may have implications for clinical therapeutics.
Direct association between orbitofrontal atrophy
and the response of psychotic symptoms to olanzapine in schizophrenia.
Molina V, Sanz
J, Benito C, Palomo T.
Int Clin Psychopharmacol. 2004 Jul;19(4):221-8.
The study of cerebral variables associated with response to neuroleptics holds
interest from both theoretical and clinical points of view. To date, no studies
have aimed to identify predictors of response to olanzapine based on cerebral
measurements. Here, we used magnetic resonance to assess the relationship
between volumes of the prefrontal (dorsolateral and orbitofrontal) and temporal
(temporal lobe and hippocampus) cortical regions and ventricles and, on the
other hand, the response to olanzapine in 16 schizophrenic patients. Data from
42 healthy controls were used to calculate volume residuals in the patients,
defined as deviations from the expected values, given individual age and
intracranial volume. Residuals thus represent the effect of illness on regional
measurements. The association between clinical change and those residuals was
calculated separately for the positive, negative and total scores from the
Positive and Negative Syndrome Scale (PANSS). There was a significant direct
association between the degree of orbitofrontal atrophy and the improvement of
positive symptoms with olanzapine. No predictors were found for change in the
negative dimension. A trend was found for patients with larger ventricles to
show a greater global decrease in total PANSS scores. Neither age nor duration
of illness explained a significant proportion of the symptom improvement. This
result, together with others from the literature, supports the idea that
atypical antipsychotics may offer some benefit to patients with significant
regional atrophy, and this may have implications for the choice of
antipsychotic in clinical practice.
Andrea
Schmitt, Katrin Wilczek, Kaj Blennow, Athanasios Maras, Alexander Jatzko, Georg
Petroianu, Dieter F. Braus and Wagner F. Gattaz
Biological Psychiatry .Volume 56, Issue 1 , 1 July 2004, Pages
41-45
Background
Membrane
lipids are important mediators of neuronal function. In a postmortem study, we
measured membrane lipid components in the left thalamus of schizophrenic
patients. This region might play an important role in the pathophysiology of
schizophrenia and has not been studied thus far with respect to its membrane
lipid composition.
Methods
The
study included 18 chronic schizophrenic patients and 23 healthy control
subjects. Using lipid extraction and thin-layer chromatography, we measured
membrane phospholipids, galactocerebrosides 1 and 2, and sulfatides in thalamus
homogenate.
Results
The main
membrane phospholipid phosphatidylcholine and the major myelin membrane
components sphingomyelin and galactocerebrosides 1 and 2 were found to be
decreased in schizophrenic patients. In contrast, phosphatidylserine was
increased. These lipid contents did not correlate with postmortem intervals and
medication doses. There was no difference in the membrane phospholipids
lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and
phosphatidylglycerol or in sulfatides.
Conclusions
Our
results confirm findings of magnetic resonance imaging, postmortem, and gene
expression studies. They support the notion of an increased phospholipid
breakdown in schizophrenia as a sign for decreased myelination and
oligodendrocyte dysfunction.
Early extrapyramidal side-effects as risk factors
for later tardive dyskinesia: a prospective study
Perminder Sachdev
Australian and New Zealand Journal
of Psychiatry 2004; Volume: 38 Number: 6 Page: 445 -- 449
Objective:
To determine whether acute neuroleptic-induced parkinsonism and akathisia were
risk factors for the later development of tardive dyskinesia (TD) in patients
on typical neuroleptics. Method:
Of 100 subjects examined for parkinsonism and akathisia after the initiation of
typical neuroleptic medication, 78 were followed up for TD after a mean 41.2
months. Results:
Nine (11.5%) subjects were diagnosed with TD, predominantly manifesting as
oro-facial dyskinesia. They had greater severity of parkinsonism and akathisia
at baseline, and a larger neuroleptic load, than those who did not develop TD.
On regression analyses, parkinsonism at baseline was a significant predictor of
later TD. Examined independently of parkinsonism, akathisia severity at 2 weeks
was also a significant predictor of later TD. Conclusions:
Acute drug-induced parkinsonism and akathisia are both predictors of TD, with
parkinsonism having greater predictive value. Acute and tardive extrapyramidal
syndromes may share vulnerability factors.
Mitochondrial
dysfunction in schizophrenia: evidence for compromised brain metabolism and
oxidative stress
S
Prabakaran, J E Swatton, M M Ryan, S J Huffaker, JT-J Huang, J L Griffin, M
Wayland, T Freeman, F Dudbridge, K S Lilley, N A Karp, S Hester, D Tkachev, M L
Mimmack, R H Yolken, M J Webster, E F Torrey and S Bahn
Molecular
Psychiatry (2004) 9, 684-697
The
etiology and pathophysiology of schizophrenia remain unknown. A parallel
transcriptomics, proteomics and metabolomics approach was employed on human
brain tissue to explore the molecular disease signatures. Almost half the
altered proteins identified by proteomics were associated with mitochondrial
function and oxidative stress responses. This was mirrored by transcriptional
and metabolite perturbations. Cluster analysis of transcriptional alterations
showed that genes related to energy metabolism and oxidative stress
differentiated almost 90% of schizophrenia patients from controls, while
confounding drug effects could be ruled out. We propose that oxidative stress
and the ensuing cellular adaptations are linked to the schizophrenia disease
process and hope that this new disease concept may advance the approach to
treatment, diagnosis and disease prevention of schizophrenia and related
syndromes.
John H Shale; Christopher M Shale; William D Mastin
Expert Opinion on Drug Safety .2004,
vol. 3, no. 4, pp. 369 - 378
By the year 2000, droperidol had become a standard
drug for the treatment of behavioural emergencies in both psychiatric and
medical settings. In 2001, the US FDA issued a 'black box' warning, citing
cases of QT prolongation and/or torsades de pointes. As a result, the use of
droperidol has been sharply circumscribed. The authors will review the
literature on antipsychotic medications in general, focusing on droperidol in
particular, with regard to QT interval prolongation, dysrhythmia, and sudden
death. In addition, the mechanism of drug-induced QT interval prolongation will
be discussed. The authors will then review their extensive experience with
droperidol. The authors conclude that, while in theory droperidol may prolong
the QT interval to an extent similar to thioridazine, its long history of
clinical use has shown no pattern of sudden deaths analogous to those that
provoked the FDA warning. Although the numbers presented by the FDA initially
appear alarming, after further evaluation it is clear that more definitive
studies should have been carried out. Droperidol is safe, extremely effective,
and now underused as a treatment for severely agitated or violent patients.