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At least 19 recordsLinked to original sources

PubMed2026

Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis.

BACKGROUND: Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition. METHODS: In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method. RESULTS: The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = -0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship. CONCLUSIONS: Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.

Humans↗

PubMed2026

Neurometabolites and Antipsychotic Response in Psychosis: A Mega-Analysis.

IMPORTANCE: Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. OBJECTIVE: To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. DATA SOURCES: Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. STUDY SELECTION: Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. DATA EXTRACTION AND SYNTHESIS: Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses. MAIN OUTCOMES AND MEASURES: Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia. RESULTS: The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P = .02), glutamate plus glutamine (Glass Δ = 0.29; P = .002), choline (Glass Δ = 0.22; P = .03), and myo-inositol (Glass Δ = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. CONCLUSIONS AND RELEVANCE: These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

Humans↗

PubMed1977

The effect of antipsychotic drugs and their clinically inactive analogs on dopamine metabolism.

Changes in dopamine metabolite levels in the rat striatum and tuberculum olfactorium, following the administration of three non-antipsychotic butyrophenones (AL-499, AHR-1900 and U-25,927) and a non-antipsychotic benzazepine (SCH-12,679), were compared to the effects seen following the antipsychotics haloperidol, chlorpromazine and clozapine. The non-antipsychotics, although clinically ineffective, were reported as active in a variety of animal screening tests. Haloperidol, chlorpromazine and clozapine produced a dose-dependent increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both regions. Of the non-antipsychotic drugs only AHR-1900 significantly elevated the level of DOPAC, however, the slope of its dose-response curve was atypically flat in comparison to the dose-response curves of drugs with known antipsychotic efficacy. Moreover, the maximal effect of AHR-1900 observed at a dose of 40 mg/kg was less than the ED50 effect of haloperidol which occurs at a 250 fold lower dose. It is concluded that the dose-dependent elevation of DOPAC in the striatum and tuberculum olfactorium of the rat is a good predictor of antipsychotic efficacy.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2026

Efficacy and Safety of GLP-1 Receptor Agonists for the Management of Antipsychotic-Induced Weight Gain.

OBJECTIVE: The objective of this systematic review and meta-analysis was to compare the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists for the management of antipsychotic-induced weight gain. DATA SOURCES: A systematic review was conducted following PRISMA methodology through July 2025 that evaluated the efficacy and safety of GLP-1 agonists for the management of antipsychotic-induced weight gain. STUDY SELECTION AND DATA EXTRACTION: Efficacy endpoints were change in body weight (kg), change in body mass index (BMI) (kg/m2), and change in HbA1c (%). The safety endpoint was gastrointestinal (GI) adverse effects. A P-value of 0.05 was considered statistically significant, and heterogeneity was reported as I2. DATA SYNTHESIS: Six studies were included in this systematic review, of which 4 trials were included in the meta-analysis. The difference found between GLP-1 agonists and placebo was a change in weight of -5.85 kg (P = 0.0622, 95% CI = -9.72 to -1.97), a change in BMI of -2.11 kg/m2 (P = 0.7692, 95% CI = -5.51 to 1.29), and a change in HbA1c of -1.58 (P = 0.6659, 95% CI = -4.75 to 1.58). The overall risk ratio for a patient to experience a GI-related adverse effect when taking a GLP-1 agonist compared to placebo was 1.83 (95% CI = 1.42 to 2.37). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: While the efficacy endpoints did not reach significance, this meta-analysis shows that select GLP-1 receptor agonists may be used to promote weight loss in patients taking antipsychotics. Controlling antipsychotic-induced weight gain helps patients remain adherent to therapeutic doses of their antipsychotic medications. CONCLUSION: The use of certain GLP-1 agonists may be considered to help promote weight loss in patients experiencing antipsychotic-induced weight gain.

Humans↗

PubMed2026

Pharmacological Interventions for Weight Reduction in Patients With Schizophrenia Treated With Antipsychotics: A Systematic Review and Network Meta-Analysis.

IMPORTANCE: Significant weight gain is a concerning adverse effect of antipsychotic medications experienced by patients with schizophrenia spectrum disorders (SSDs). Its high prevalence and significant contribution to cardiometabolic morbidity in this population warrant better consensus on the management of antipsychotic-induced weight gain and related comorbidity. OBJECTIVES: To evaluate the association between pharmacological interventions and changes in body weight among antipsychotic-treated patients with SSDs. DATA SOURCES: Ovid MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, ClinicalTrials.gov, and the International Clinical Trials Registry Platform (ICTRP) Search Portal were searched up to December 5, 2025. STUDY SELECTION: Randomized clinical trials examining any pharmacological intervention for weight reduction in antipsychotic-treated patients with SSDs were included. No restrictions to study duration were applied. DATA EXTRACTION AND SYNTHESIS: A systematic review and frequentist random-effects network meta-analysis was conducted. Certainty in the evidence was assessed using the Confidence in Network Meta-Analysis (CINeMA) tool. The first round of data analysis took place between May 2025 to November 2025 and was updated in December 2025. MAIN OUTCOMES AND MEASURES: The primary outcome was change in body weight following treatment with pharmacological agent vs placebo or standard care. Secondary outcomes included other anthropometric and metabolic parameters. RESULTS: A total of 95 studies examining 39 individual pharmacological interventions were included in this review (pooled N = 5898). The network meta-analysis found that semaglutide (mean difference [MD], -10.98 kg; 95% CI, -13.33 to -8.62; k = 3; moderate certainty), liraglutide (MD, -5.43 kg; 95% CI, -8.54 to -2.33; k = 2; moderate certainty), topiramate (MD, -3.95 kg; 95% CI, -5.89 to -2.02; k = 5; moderate certainty), metformin (MD, -3.86 kg; 95% CI, -5.02 to -2.70; k = 16; moderate certainty), and exenatide (MD, -2.97 kg; 95% CI, -5.83 to -0.11; k = 3; moderate certainty) were associated with the most significant reductions in body weight compared to placebo. Other interventions including ramelteon, nizatidine, and aripiprazole were also found to be associated with weight-reducing effects but with very low certainty of evidence. Clinically meaningful weight change of 5% or greater was observed with semaglutide and metformin. Beneficial effects on other metabolic outcomes were also noted with several of the medications, and there were no major concerns with gastrointestinal adverse effects or leaving the study early (ie, dropouts) between interventions. CONCLUSIONS AND RELEVANCE: This systematic review and network meta-analysis found substantial variability in weight-related outcomes across pharmacological interventions for antipsychotic-treated individuals with SSDs. Semaglutide, liraglutide, topiramate, metformin, and exenatide were associated with the greatest reductions in body weight and were supported by the highest-certainty evidence, providing guidance for clinicians managing antipsychotic-associated weight gain.

Humans↗

PubMed1978

Fluphenazine decanoate vs oral antipsychotics: a comparison of their effectiveness in the treatment of schizophrenia as measured by a reduction in hospital readmissions.

A significant number of chronic psychotic patients are readmitted to state mental hospitals each year due in large part to their inability or unwillingness to continue taking antipsychotic medication on a voluntary basis. This paper describes an ex post facto study comparing the effectiveness of fluphenazine decanoate, a long acting antipsychotic medication, with a variety of oral antipsychotics in reducing the number of readmissions of two groups of chronic psychotic patients to a state operated mental health facility. The results demonstrated that a group of 61 patients receiving fluphenazine decanoate had signigicantly fewer readmissions during the one year study period than did a comparison group on oral antipsychotics. The findings indicate that long acting antipsychotic medication, as part of an intensive outpatient treatment program, strongly militates against the tendency of chronic psychotic patients to discontinue treatment.

Administration, Oral↗

PubMedDate not supplied

Plasma level monitoring of antipsychotic drugs.

Psychotic patients treated with identical doses of antipsychotic drugs have been shown to have great interindividual differences in their steady state plasma concentration. Therefore, monitoring treatment by dosage adjustment alone is of little value. If antipsychotic blood levels can be related to clinical response then their routine measurement may well result in well defined guidelines to individualised optimal dosage. Despite the considerable effort expended in this field and the many interesting testable hypotheses generated, little substantive evidence for an acceptable plasma level monitoring guide has been reported to date. Work on metabolite level profiles, intra- and extracellular drug concentration differences, more detailed clinical rating scales, and improved experimental design, all show great promise for the future. Investigation of the pharmacokinetics and the elucidation of the often complex metabolic pathways of individual antipsychotic drugs are generating the data base required for the rational pharmacotherapy of these most severely ill patients. Until more data are available, routine monitoring of antipsychotic drug plasma levels remains of research interest.

Antacids↗

PubMed1978

Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent.

Loxapine is a dibenzoxazepine, tricyclic compound recommended for the treatment of acute and chronic schizophrenia. In its therapeutic effectiveness and profile and incidence of side-effects, loxapine closely resembles the traditional antipsychotic agents. Although loxapine has tended to be less effective than some standard antipsychotic drugs in a few short-term (3 to 4 weeks) studies, it has been superior to a placebo and about as effective as chlorpromazine, haloperidol, trifluoperazine or thiothixene when evaluated after 4 to 12 weeks. Like the phenothiazine (e.g. chlorpromazine) and butyrophenone (e.g. haloperidol) antipsychotic agents, loxapine causes a high incidence of extrapyramidal reactions. Sedation occurs frequently, especially during early stages of treatment. Other, less common side-effects such as anticholinergic effects (dry mouth, blurred vision, etc.), hypotension, tachycardia and precipitation of epileptic seizures, which occur with the older antipsychotic drugs, have also been reported with loxapine.

Animals↗

PubMed1977

Perlapine: relationship between stimulation of prolactin secretion and antipsychotic activity.

Perlapine is a dibenzohetereopine compound chemically related to clothiapine, loxapine, and clozapine. Although the latter three compounds are antipsychotic, perlapine has not been reported to be antipsychotic. Nevertheless, all four drugs increase rat plasma prolactin levels. The order of potency is loxapine, perlapine, clothiapine, and clozapine. These results suggest that either perlapine should be reexamined for antipsychotic properties or there are hitherto unsuspected discrepancies between the dopamine receptors relevant to antipsychotic activity in man and those that regulate prolactin secretion in the rat.

Animals↗

PubMed1976

Antipsychotic drugs and dopamine-mediated responses in Aplysia neurons.

The effect of antipsychotic drugs was tested on responses to micro-electrophoretically applied dopamine, acetylcholine and 5-hydroxytryptamine in identified neurons of the marine gastropod Aplysia californica. Fluphenazine was able to depress the response to DA in concentration of 10 muM, with 100 muM DA-responses of many neurons were blocked completely. Thioridazine (10 and 100 muM) and haloperidol (50 muM) were also effective in depressing DA-responses, while the non-antipsychotic phenothiazines mepazine (10 and 100 muM) and promethazine (100 muM) had only a slight action on DA-receptors. ACh- and 5-HT-responses were slightly affected only by high concentrations after long lasting perfusion. The investigated drugs had no persistent or only an insignificant effect on resting membrane potential and amplitude of action potentials of the neurons. With haloperidol depolarizing afterpotentials leading to double discharges were observed in some neurons. In a few instances spontaneous EPSPs disappeared with the DA-response under the influence of anti-psychotic drugs. The results render a direct neurophysiological evidence for the blockade of DA-receptors by antipsychotic drugs in correspondence to their clinical efficacy and agree with data from clinical observations and obtained in neurochemical, behavioral and indirect neurophysiological experiments.

Acetylcholine↗

PubMed1976

The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics.

The cyclic AMP generating system in slices of the rat limbic forebrain was investigated. In consists of: (u) A noradrenergic system which responds to norepinephrine (NE) and isoproterenol. Though the rise of the nucleotide elicited by isoproterenol is more rapid than that caused by NE, the maximal effect is less than half of that induced by NE; (2) an adenosine-dependent system. The noradrenergic cyclic AMP generating system in the limbic forebrain displays a number of properties of a central NE receptor: it develops supersensitivity to NE and isoproterenol following prolonged deprivation of NE at postsynaptic sites (chronic treatment with reserpine or chemosympathectomy with 6-hydroxydopamine). When noradrenergic terminals are protected from 6-hydroxydopamine by desmethylimipramine, the responses to NE are not enhanced. Responses to NE are blocked by both propranolol and phentolamine, while responses to isoproterenol are blocked by propranolol but not by phentolamine. The adenosine-dependent system does not develop supersensitivity after central chemosympathectomy and is not blocked by either alpha- or beta-antagonists. While not altering the basal level of the nucleotide, clinically effective antipsychotic drugs caused a dose-dependent inhibition of the limbic noradrenergic cyclic AMP response with clozapine and pimozide being particularly potent (IC50 0.06 and 0.08 muM, respectively). Antipsychotic drugs do, however, not affect cyclic AMP responses elicited by adenosine. The results are compatible with the view that the central NE receptor is closely related to or may be an integral part of an adenylate cyclase system and that its blockade in the limbic forebrain by antipsychotic drugs may contribute to their therapeutic action.

Adenosine↗

PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. I. Role of adrenergic system.

The activity of serotonergic (5HT) neurons in the dorsal raphe nucleus was inhibited by the i.v. administration of certain antipsychotic drugs (methiothepin, clozapine and thioridazine). However, other antipsychotic agents (chlorpromazine, haloperidol and pimozide) did not inhibit raphe cell firing. The inhibitory potency of these drugs on raphe activity correlates with reported central noradrenergic blocking efficacy. An alpha-adrenergic blocking agent, piperoxane, but not the beta-blocking agents, propranolol and MJ 1999, inhibited raphe activity when administered systemically. All of these drugs appear to act indirectly since they (and NE) have relatively weak or variable effects when applied microiontophoretically to raphe neurons. The depressant effects of certain antipsychotic drugs and piperoxane on 5HT neurons appears to be mediated by a cnetral adrenergic system since (1) the depression could be reversed by the catecholamine releasing agents 1- and d-amphetamine; (2) the depression could be abolished by destruction of adrenergic pathways in the CNS by chemical, mechanical, or electrothermic lesions. While a precise localization has not yet been obtained, the data suggest that these drug effects may be mediated by an adrenergic pathway ascending from the lower brainstem.

Animals↗

PubMed1976

Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin.

As reported in the preceding study, the ability of certain antipsychotic and adrenolytic agents to inhibit the spontaneous firing of serotonergic 5HT neurons in the dorsal raphe nucleus appeared to be related to adrenergic blocking efficacy. However, the interaction between adrenergic and serotonergic systems was apparently indirect. In this phase of the study we investigated the hypothesis that another transmitter system could mediate this interaction. We examined the effects of two inhibitory amino acid transmitters (GABA and glycine) for possible effects on dorsal raphe cell firing using single cell recording and microiontophoretic techniques. In addition, the ability of the GABA antagonist, picrotoxin and the glycine antagonist, strychnine to reverse the effects of the antipsychotic and alpha-blocking drugs on dorsal raphe firing was tested. Both GABA and glycine were found to inhibit raphe cell firing selectively, allowing for a possible neurotransmitter function for these amino acids within the dorsal raphe nucleus. However, picrotoxin but not strychnine was found to reverse the effects of the antipsychotic and alpha-blocking drugs on raphe firing. Based on these results, we propose that the adrenergic input may influence 5HT neurons indirectly via a GABAergic interneuron or interposed GABA neuron.

Animals↗

PubMed1977

Perlapine and dopamine metabolism: prediction of antipsychotic efficacy.

A model for the prediction of antipsychotic efficacy based on the dose-dependent increase in levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and tuberculum olfactorium of the rat is presented. The effect of perlapine, a sleep-promoting and sedative agent reported to lack antipsychotic efficacy, was compared in this system to haloperidol, chlorpromazine and clozapine. All four drugs produced a dose-dependent increase in DOPAC in the two dopamine-rich structures. The potency of perlapine was similar to that of chlorpromazine. Dopamine, assayed in the striatum and tuberculum olfactorium by a new gas chromatographic procedure was not altered by perlapine. The time--action curves for perlapine and clozapine were virtually identical both in the striatum and in the tuberculum olfactorium. All four drugs also elevated homovanillic acid to a similar extent. These results indicate that perlapine should be re-evaluated clinically. We predict that such trials will reveal that perlapine does possess antipsychotic efficacy.

Animals↗

PubMed1979

The "neuroleptic" antipsychotic drugs. 1. Mechanisms of action.

The antipsychotic drugs have provided effective and relatively safe treatment of schizophrenia, paranoid illnesses, and manic-depressive conditions marked by psychotic features. These agents are sometimes called "neuroleptic," as virtually all produce signs of extrapyramidal neurologic disorders in addition to their antipsychotic actions; in part, evidently, the neuroleptic effects are an artifact of the means of screening of potential new agents. These agents have a strong and selective antagonistic action on synaptic mechanisms in the brain mediated by dopamine as a neurotransmitter. This antidopamine action almost certainly contributes importantly to their parkinsonism effect (basal ganglia) and their prolactin-elevating (hypothalamic) effect; in addition, antipsychotic actions may be mediated by antidopamine effects, possibly in limbic and other forebrain centers.

Animals↗

PubMed1976

Maintenance antipsychotic therapy: is the cure worse than the disease?

The serious long-term complications of maintenance antipsychotic therapy led the authors to undertake a critical review of outpatient withdrawal studies. Key findings included the following: 1) for a least 40% of outpatient schizophrenics, drugs seem to be essential for survival in the community; 2) the majority of patients who relapse after drug withdrawal recompensate fairly rapidly upon reinstitution of antipsychotic drug therapy; 3) placebo survivors seem to function as well as drug survivors--thus the benefit of maintenance drug therapy appears to be prevention of relapse; and 4) some cases of early relapse after drug withdrawal may be due to dyskinesia rather than psychotic decompensation. The authors urge clinicians to evaluate each patient on maintenance antipsychotic therapy in terms of feasibility of drug withdrawal and offer practical guidelines for withdrawal and subsequent management.

Antipsychotic Agents↗

PubMed1979

Antipsychotic drugs and seizures.

The authors examine the clinical problem of which antipsychotic drug to use when antipsychotics are indicated in patients with a seizuire disorder or who are susceptible to seizures. While definitive answers to this problem are still unknown, guidelines are offered for antipsychotic drug use in this situation, based on the author's understanding of psychotropics and epilepsy.

Adolescent↗

PubMed1977

Antipsychotic effects, side effects and effective dosis of the butyrophenone lenperone (AHR 2277).

Three open studies with Lenperone were performed. 50 hospitalized schizophrenic patients were treated 20-30 days with Lenperone. The therapeutic effective dose was 30-50 mg/day. The highest daily dosage was 90 mg. Patients were examined on fixed observation days and the findings were documented by means of the AMP system. AMP data were analyzed at symptom and syndrome level and compared using an analysis of covariance. In the described dosage Lenperone acted only little sedating, strong antipsychotic and caused only a few single extrapyramidal and little autonomic side effects. The dosage is limited because of the effect on heart and blood circulation. Lenperone caused a good improvement of depressive symptoms in the schizophrenic patients. Lenperone was well tolerated and slowed a rapid onset of its antipsychotic effect. It caused a steady improvement of productive schizophrenic symptoms. For better knowledge of the profile of the effects of Lenperone, a trial in depressive paranoid syndromes, for example schizoaffective psychoses, would be interesting; a double-blind trial in comparison to a well-known antipsychotic would be very useful.

Adult↗