lithium-chloride and Schizophrenia

Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BD). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), 1 microM serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [35S]GTPgammaS binding to membrane Galpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [35S]GTPgammaS binding to Galpha proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPgammaS binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Blood Platelets; Enzyme Activation; Female; GTP-Binding Proteins; Humans; Lithium Chloride; Male; Protein Kinase C; Schizophrenia; Signal Transduction; Valproic Acid

The safety and tolerability of clozapine combined with lithium were investigated because of potential additive risks as well as frequent usage in clinical practice. Ten hospitalized schizophrenic and 10 schizoaffective patients receiving clozapine maintenance therapy with partial therapeutic response were studied in a randomized controlled trial. CGI and PANSS outcome ratings were employed and a cognitive battery was administered at baseline and after 4 weeks of lithium and placebo administration. Barnes and UKU side effect ratings and laboratory safety data were obtained. Combined lithium-clozapine treatment was well tolerated except for reversible neurotoxic reactions in two schizophrenic patients. Safety measures showed no significant variations, even during lithium toxicity. Total WBC and absolute granulocyte counts increased with lithium and declined with placebo. Schizoaffective patients improved with lithium on CGI and PANSS total and negative symptom scales and the cognitive measures, whereas schizophrenic patients did not. Lithium added to clozapine in treatment regimens for hospitalized, treatment-resistant, schizoaffective patients appears to afford potential benefit without harmful effects; for schizophrenic patients, however, it did not afford improvement but posed a risk of lithium toxicity.

Topics: Adult; Analysis of Variance; Clozapine; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Psychotic Disorders; Schizophrenia

Lithium-associated remission of psychosis has been described in schizophreniform disorders and in psychotic patients with variants of the red blood cell (RBC)/lithium ratio. To determine whether such remissions are the consequence of lithium treatment rather than spontaneous in nature, a double-blind, placebo-controlled study was undertaken in 16 psychotic patients preselected for the variant of RBC/lithium ration and/or DSM-III schizophreniform diagnosis. Essentially full and sustained remission of psychosis began during periods of lithium treatment in 4 of 15 of the study patients. Improvement was significantly greater during lithium treatment periods than in counterbalanced placebo treatment conditions in these four subjects (p less than 0.02). Fifteen of the same 16 study patients failed to initiate sustained improvement either spontaneously or while on placebo during the initial 14-day treatment period. In this preselected psychotic population, sustained response to lithium occurred at a rate at least four times greater than that which could be attributed to spontaneous remission.

Topics: Affective Disorders, Psychotic; Chlorides; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Haloperidol; Humans; Lithium; Lithium Chloride; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function.. To investigate the physical interaction and functional modulation between D1R and GSK-3β.. D1R and GSK-3β physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3β impaired D1R activation along with a decrease in D1R-GSK-3β interaction. GSK-3β inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of β-arrestin-2. Similarly, inhibition of GSK-3β in rat PFC also resulted in impaired D1R activation and association with GSK-3β. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3β activity and D1R-GSK-3β association and decreased D1R activation in the PFC.. The present work identified GSK-3β as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3β-regulated D1R function which may underlie D1R dysfunction in schizophrenia.

Topics: Adjuvants, Immunologic; Animals; beta-Arrestins; Cyclic AMP; Disease Models, Animal; Dopamine Agonists; Endocytosis; Enzyme Inhibitors; Fenoldopam; Glycogen Synthase Kinase 3 beta; Guanosine 5'-O-(3-Thiotriphosphate); HEK293 Cells; Humans; Indoles; Lithium Chloride; Maleimides; Prefrontal Cortex; Protein Transport; Rats; Receptors, Dopamine D1; Schizophrenia

Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia.

Topics: Aggression; Animals; Antipsychotic Agents; Anxiety; Clozapine; Disease Models, Animal; Female; Lithium Chloride; Mice; Mice, Inbred C57BL; Phenotype; Schizophrenia; Schizophrenic Psychology; Social Isolation; Suicidal Ideation; Suicide Prevention

Latent inhibition (LI) is a measure of cognitive gating and refers to reduced conditioned learning when there is pre-exposure to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (US). Dysregulation of LI is associated with some neuropsychiatric disorders, including schizophrenia, and the ability to facilitate LI in rodents is a reasonably good predictive test for antipsychotic drugs. Converging evidence supports neurotensin-1 receptor (NTS1) agonists as novel drugs for schizophrenia. Therefore, we investigated the ability of a brain-penetrating, selective NTS1 agonist, PD149163, to facilitate LI in heterozygous Brattleboro rats, a strain that exhibits naturally low LI. Conditioned taste aversion to flavored water (FW; 0.1% saccharin) was induced by pairing it with malaise-inducing injections of lithium chloride (LiCl). Prior to LiCl-FW pairing, rats received subcutaneous injections of saline, or PD149163 (100 µg/kg or 200 µg/kg). Half the rats in each drug group had been allowed to drink FW the day before the LiCl-FW pairing (pre-exposed rats). Two days after pairing, the amount of FW each rat consumed was recorded. LI, defined as significantly greater FW drinking in the pre-exposed group compared with the non pre-exposed group, was exhibited only among rats that received 200 µg/kg of PD149163. These results further support NTS1 agonists as potentially novel drugs for the treatment of schizophrenia.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Brain; Conditioning, Classical; Conditioning, Psychological; Lithium Chloride; Male; Rats; Rats, Brattleboro; Receptors, Neurotensin; Schizophrenia

Patients with schizophrenia are at increased risk of suicide, but data from controlled studies of pharmacotherapy in relation to suicide risk is limited.. To explore suicide risk in schizophrenia in relation to medication with antipsychotics, antidepressants, and lithium.. Of all patients with a first clinical discharge diagnosis of schizophrenia or schizoaffective disorder in Stockholm County between 1984 and 2000 (n=4000), patients who died by suicide within five years from diagnosis were defined as cases (n=84; 54% male). Individually matched controls were identified from the same population. Information on prescribed medication was retrieved from psychiatric records in a blinded way. Adjusted odds ratios [OR] of the association between medication and suicide were calculated by conditional logistic regression.. Lower suicide risk was found in patients who had been prescribed a second generation antipsychotic (clozapine, olanzapine, risperidone, or ziprasidone; 12 cases and 20 controls): OR 0.29 (95% confidence interval [CI], 0.09-0.97). When the 6 cases and 8 controls who had been prescribed clozapine were excluded, the OR was 0.23 (95% CI 0.06-0.89). No significant association was observed between suicide and prescription of any antipsychotic, depot injection antipsychotics, antidepressants, SSRI, or lithium.. Lower suicide risk for patients who had been prescribed second generation antipsychotics may be related to a pharmacological effect of these drugs, to differences in adherence, or to differences in other patient characteristics associated with lower suicide risk.

Topics: Adolescent; Adult; Age Factors; Antidepressive Agents; Antipsychotic Agents; Case-Control Studies; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Risk; Schizophrenia; Schizophrenic Psychology; Self-Injurious Behavior; Sex Factors; Suicide; Young Adult

Bipolar disorder and schizophrenia share common pathophysiological processes and may have similar perceptual abnormalities. Mismatch negativity (MMN) and P3a - event-related potentials associated with auditory preattentional processing - have been extensively studied in schizophrenia, but rarely in bipolar disorder. Furthermore, MMN and P3a have not been examined between diagnostic subgroups of patients with bipolar disorder. We evaluated MMN and P3a in patients with bipolar disorder compared to patients with schizophrenia and healthy controls.. MMN and P3a were assessed in 52 bipolar disorder patients, 30 schizophrenia patients, and 27 healthy control subjects during a duration-deviant auditory oddball paradigm.. Significant MMN and P3a amplitude reductions were present in patients with bipolar disorder and schizophrenia relative to controls. The MMN reduction was more prominent in patients with schizophrenia than bipolar disorder, at a trend level. P3a did not differ significantly between patient groups. There were no MMN or P3a differences between patients with bipolar I (n = 34) and bipolar II (n = 18) disorder. Patients with bipolar I disorder failed to show lateralized MMN, in contrast to the other groups. No MMN or P3a differences were found between patients with bipolar disorder taking (n = 12) and not taking (n = 40) lithium, as well as between those taking (n = 30) and not taking (n = 22) antipsychotic medications.. Patients with bipolar disorder showed deficits in preattentive auditory processing, including MMN deficits that are less severe and P3a deficits that are slightly more pronounced, than those seen in schizophrenia.

Topics: Acoustic Stimulation; Adult; Analysis of Variance; Bipolar Disorder; Brain Mapping; Contingent Negative Variation; Electroencephalography; Event-Related Potentials, P300; Female; Functional Laterality; Humans; Lithium Chloride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Several studies have suggested mitochondrial abnormality in bipolar disorder (BD) and schizophrenia (SZ). We have previously reported the decreased expression of mitochondrial complex I subunit gene, NDUFV2 at 18p11, in lymphoblastoid cell lines (LCLs) from Japanese patients with bipolar I disorder (BDI). Recently it was reported that no differences were found in NDUFV2 mRNA levels in LCLs of Caucasian BDI patients compared with controls. In this study, we tested the altered expression of NDUFV2 in extended Japanese LCLs and LCLs from different ethnic groups. Similar tendency was found in the current study compared with our previous study, since decreased expression of NDUFV2 in LCLs from Japanese patients with BDI was found (p=0.03). We also found that the expressions of NDUFV2 were up-regulated in those from patients with Japanese bipolar II disorder (p=0.001) and the mRNA levels of this gene were down-regulated in Caucasian SZ (p=0.000001) compared with controls. Furthermore, we revealed that the mRNA expression of NDUFV2 in LCLs cultured with valproate, one of mood stabilizers, were significantly increased compared with controls (p=0.02). Our study presented the further evidence of biological significance of NDUFV2 in BD and SZ.

Topics: Adult; Aged; Aged, 80 and over; Antimanic Agents; Bipolar Disorder; Cell Line, Transformed; Female; Gene Expression; Genotype; Humans; Lithium Chloride; Lymphocytes; Male; Middle Aged; NADH Dehydrogenase; RNA, Messenger; Schizophrenia; Statistics, Nonparametric; Up-Regulation; Valproic Acid

The involvement of mesostriatal dopaminergic neurons in cognitive operations is not well understood, and needs to be further clarified. The use of latent inhibition paradigms is a means of investigating cognitive processes. In this study, we investigated the involvement in latent inhibition of dopaminergic inputs in the anterior part and posterior part of the dorsal striatum. The latent inhibition phenomenon was observed in a conditioned olfactory aversion paradigm. Changes in extracellular dopamine levels induced by the conditioned olfactory stimulus (banana odor) were monitored in the two parts of the dorsal striatum in the left hemisphere after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. During the conditioning session animals received either an i.p. injection of NaCl (0.9%) (control groups) or an i.p. injection of LiCl (0.15 M) (conditioned groups). Dopamine variations and place preference or aversion toward the stimulus were analyzed simultaneously in pre-exposed and non-pre-exposed animals. Data collected during the retention (test) session were as follows. Where the anterior part of the striatum was concerned, similar enhancements in dopamine levels (+100%) were obtained in pre-exposed and non-pre-exposed control animals, as well as in the pre-exposed experimental animals. In contrast, dopamine levels in the non-pre-exposed experimental group (conditioned animals) remained fairly consistently close to the baseline after the presentation of the olfactory stimulus. Where the posterior part of the striatum was concerned, increases in extracellular dopamine levels were similar (+50%) for the different groups. The present results suggested that dopaminergic neurons reaching the anterior part of the dorsal striatum are implicated in the latent inhibition phenomenon and affective perception, whereas dopaminergic terminals in the posterior part of the dorsal striatum appeared to be involved neither in latent inhibition nor in affective perception of the stimulus, seeming only to be affected by the intrinsic properties of the stimulus. Cognitive as well as affective deficits have been reported in patients with schizophrenia. Thus the present data may be considered in the context of the pathophysiology of schizophrenic psychoses.

Topics: Affect; Afferent Pathways; Animals; Avoidance Learning; Behavior, Animal; Cognition; Conditioning, Psychological; Dopamine; Lithium Chloride; Male; Neostriatum; Neural Inhibition; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Schizophrenia; Smell

Cultured fibroblasts were prepared from six normal controls, five DSM-III manic patients, and six DSM-III schizophrenic patients. Lithium (Li+) uptake, 24-hour Li+ ratios, and steady-state membrane potential were measured in these cell lines. The uptake of 10 mM Li+ reached maximum at 2 hours, with an intracellular concentration of approximately 15 mM. No significant difference in uptake was found among subject groups. Twenty-four hour Li+ (ratio of intracellular/extracellular Li+) ratios were determined by incubating the cell lines for 24 hours in the presence of 2 mM Li+. No significant difference was observed among groups; nor was there any significant correlation between the fibroblast 24-hour ratios and 24-hour in vitro ratios determined in donor red cells. The relationship between membrane potential and the 24 hour Li+ ratio in fibroblasts was determined. The average potential in these cell lines was -56 mV and was not affected by Li+ treatment. No correlation between the Li+ ratio and membrane potential was found.

Topics: Adult; Bipolar Disorder; Chlorides; Circadian Rhythm; Erythrocytes; Fibroblasts; Humans; Lithium; Lithium Chloride; Membrane Potentials; Schizophrenia

The pharmacokinetics of lithium were determined in eight adult dogs. The data were fitted to a two-compartment model. Single intravenous doses of lithium chloride, and single oral doses of lithium carbonate were used. The mean plasma lithium half-life (t1/2) following the single intravenous dose was 21.6 h, and the mean apparent specific volume of distribution of the central compartment (V'c) was 0.189 l/kg. Mean bioavailability was 78.8% following oral administration.

Topics: Administration, Oral; Animals; Chlorides; Dogs; Female; Humans; Injections, Intravenous; Kinetics; Lithium; Lithium Carbonate; Lithium Chloride; Male; Models, Biological; Reference Values; Schizophrenia; Swine

The authors studied the changes in the activity of tyrosine hydroxylase and dopamine-beta-hydroxylase (the principal enzymes controlling the synthesis of catecholamines) in the whole brain of rabbits on intracisternal injection of immunoglobulin G isolated from the blood of brain-sensitized dogs or from the serum of schizophrenic humans. Also the changes of the content of principal catecholamines (DOPA, noradrenaline, adrenaline) in the animals brain on intravenous injection of lithium chloride after preliminary treatment of the animals with anticerebral antibodies were studied. The changes of the activity of both enzymes in both series of the experiments appeared to be uniformly directed, the fact, that gives one grounds to regard the mechanisms underlying these disturbances as similar. A positive effect of lithium on the catecholamine metabolism in the rabbit CNS was observed. This makes is possible to recommend the model used in this study for examining the efficacy and mode of action of a number of psychotropic drugs.

Topics: Animals; Antibodies; Brain; Catecholamines; Chlorides; Dogs; Dopamine beta-Hydroxylase; Humans; Lithium; Lithium Chloride; Rabbits; Schizophrenia; Tyrosine 3-Monooxygenase

Lithium hydroxybutyrate (10 mg/kg) prevents the amphetamine-induced EEG arousal and amplitude frequency alterations in the motor and visual cortex, posterior hypothalamus, midbrain reticular formation, and caudate nucleus but potentiates the action of the psychostimulant on the EEG of the hippocamp and amygdala. The response to the light flickering rhythm in the visual cortex remains within initial upon concurrent administration of both the drugs.

Topics: Amphetamine; Animals; Bipolar Disorder; Cerebral Cortex; Chlorides; Disease Models, Animal; Drug Interactions; Electroencephalography; Humans; Hydroxybutyrates; Lithium; Lithium Chloride; Organometallic Compounds; Rabbits; Schizophrenia