Antipsychotic Drug Concentrations Research Articles

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

Fatal concentrations of antidepressant and antipsychotic drugs in post-mortem femoral blood.

Antidepressants and antipsychotics are both an important class of prescription drugs within post-mortem (PM) toxicology because most of the substances are toxic in overdose and the mental disorders being treated may be associated with suicidality. A wide range of antidepressants and antipsychotics are currently included in up-to-date PM toxicology analysis protocols. However, apart from case studies, few reports on fatal concentrations based on large number of cases have been published in the literature. Based on PM investigations in Finland between 2000-2020, this study provides fatal reference concentrations in poisonings due to an antidepressant or an antipsychotic drug assigned as the principal intoxicant. Summary statistics for drug concentrations in PM femoral blood (min, max, mean, 10th, 25th, 50th, 75th, 90thpercentile) were calculated for 17 antidepressant (N = 2007) and for 12 antipsychotic drugs (N = 1161). The proportion of suicide, accident and undetermined manner of death is indicated for each drug. Further, the fatal concentrations obtained in this study were evaluated by comparison with fatal and "normal" PM concentrations reported by two previously published approaches, the grouped causes of death approach and the all causes of death approach, respectively. This study shows that, despite the well-known variation in PM drug concentrations, competently generated fatal concentration results for the drugs studied are consistent to such an extent that they can be used as a reference in the interpretation process.

Effects of Environmentally Relevant Concentrations of Antipsychotic Drugs (Sulpiride and Clozapine) on Serotonergic and Dopaminergic Neurotransmitter Systems in Octopus Brain Tissue

Pharmaceuticals and personal care products (PPCPs) from specific activities often enter surface and groundwater, adversely affecting the physiological functions of non-target organisms and posing a serious threat to a wide range of aquatic organisms. Therefore, the aim of this study was to investigate the effects of environmentally relevant concentrations of the antipsychotic drugs sulpiride and clozapine on dopaminergic (DAergic) and serotonergic (5-hydroxytryptaminergic, i.e., 5-HTergic) neurotransmitter systems in the brain of a short-arm octopus (Octopus ochellatus). Octopus ochellatus adults were exposed to environmentally relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drug on the transcription and expression levels of major functional molecules in the DAergic and 5-HTergic systems of the brain were analyzed. By antagonizing the dopamine receptor D2 (DRD2) or 5-hydroxytryptamine receptor 2A (5-HTR2A), the two drugs induced abnormal transcription and expression levels of important functional molecules in the brain’s DA and 5-HT signaling pathways. In addition, dose-dependent adverse reactions were observed with these antipsychotics. Our results suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the brain of Amphioctopus fangsiao (O. ochellatus), possibly affecting brain functions, such as reproduction, predation, camouflage, learning, and memory. As a result, they pose a serious threat to the health of Amphioctopus fangsiao.

Fatal concentrations of antidepressants and antipsychotics in post-mortem blood

The objective was to compare the summary statistics for fatal antidepressant and antipsychotic drug concentrations mined by different approaches from post-mortem (PM) toxicological data. Reference concentrations of drugs play a major part in the interpretation of PM toxicology results. However, PM drug concentrations are not necessarily the same as those at the time of death, and consequently standard tables of clinical plasma concentration data are of limited value. Compilations of PM concentrations collected from literature sources are often heterogeneous in terms of the sampling site, the analytical methods used, and the number of cases involved. However, there are also published summary statistics for drug concentrations in PM femoral venous blood, based on extensive databases from centralized laboratories with well-established and high-quality working practices. The present study establishes concentration distributions for a number of antidepressant and antipsychotic drugs, specified as a principal finding in fatal poisoning (principal finding approach). These levels are then compared with those obtained using two previous approaches: according to the all-causes-of-death (Ketola RA, Drug Test Anal, 2019, 11, 1326–1337) or according to the grouped causes of death, aka “the Druid approach”, where the reference information is subdivided into poisonings by one specific substance only, multi-substance poisonings and non-poisoning controls (Reis M, J Anal Toxicol, 2007, 31, 254-264; Söderberg C, Forensic Sci Int, 2016, 266, 91-101). Summary statistics for fatal antidepressant and antipsychotic drug concentrations in PM femoral venous blood were generated according to the principal drug finding. In most cases, also other drugs were implicated in the cause of death. The data were mined between 2000–2020 from the national PM toxicology database, maintained by the Finnish Institute for Health and Welfare, in which all results of the toxicological analyses in medico-legal investigations and information from the respective death certificates are collected. From this material, those antidepressant and antipsychotic drugs that had been quantitatively analysed at least 10 times were selected. Concentration percentiles (10th, 50th, 90th, 95th, 97.5th) were calculated for 16 different antidepressant ( N = 1999) and for 7 different antipsychotic drugs ( N = 1134), defined as principal findings of fatal poisoning by forensic pathologists. For instance, for the antidepressant amitriptyline the respective concentrations were 0.66, 2.0, 8.3, 13 and 25 mg/L, and for the antipsychotic levomepromazine (methotrimeprazine) 0.40, 1.5, 5.3, 10 and 16 mg/L. A comparison with other data mining approaches will be presented in visual form. A clear correspondence was found between, for example, the 90th percentile concentration level of the present principal finding approach and the 97.5th percentile concentration level of the all-causes-of-death approach. Similarly, a correspondence was found between, for example, the median concentration level of the present principal finding approach and the median concentration level of the multi-substance poisoning group in the Druid approach. The novel data presented in this study followed by a systematic comparison with data from previous studies helps rationalize the use of reference concentrations from various sources in the interpretation of potential poisoning deaths. Further data mining for additional drugs will be markedly easier in the principal finding approach than in the Druid approach, provided that the principal findings are specified in advance in the database as is in our case. Despite the proven usefulness of reference concentrations, interpretation must always be made on a case-by-case basis, taking into account e.g. background information, autopsy findings, and substance interactions. A forensic toxicologist must have the evidence-based PM concentration information at his or her disposal when assisting a forensic pathologist in determining the cause of death or being called to testify in court.

A novel passive sampling and sequential extraction approach to investigate desorption kinetics of emerging organic contaminants at the sediment−water interface

Forms of organic contaminants is an important driver of bioavailable fraction and desorption kinetics of pollutants binding to sediments. To determine fluxes and resupply of nine environmentally-relevant antipsychotic drugs, which are emerging pollutants that can have adverse effects on aquatic organisms, interface passive samplers of diffusive gradients in thin films (DGT) were deployed for 21 days, in situ at the sediment-water interface in submerged sandy riverbank sediments. At each deployment time, samples of sediment were collected and subjected to consecutive extraction of pore water, as well as rapidly-desorbing (labile), stable-desorbing, and bound residue fractions. Concentrations of antipsychotic drugs decreased with sediment depth with the greatest concentrations observed in the top 2 cm. Positive fluxes of antipsychotic drugs were observed from sediment to surface water. The dynamic fraction transfer model indicated that the labile fraction can be resupplied with a lag time (> 21 d). When results were further interpreted using the DGT-induced fluxes in soils and sediments (DIFS) model, partial resupply of antipsychotic drugs from sediment particles to porewater was demonstrated. Desorption occurred within the entirety of the observed 15 cm depth of sediment. Fastest rates of resupply were found for carbamazepine and lamotrigine. Size of the labile pool estimated by the DIFS model did not fully explain the observed resupply, while a first-order three-compartment kinetic model for the fast-desorbing fraction can be used to supplement DIFS predictions with estimations of labile pool size.

The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia.

Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D-mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non-interventional manner. Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. We observed a negative relationship between vitamin D and dose-adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose-normalized drug concentrations of aripiprazole and quetiapine. Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

Infection is associated with elevated serum concentrations of antipsychotic drugs.

We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.

Concentration-Effect Relationships of Psychoactive Drugs and the Problem to Calculate Therapeutic Reference Ranges.

Despite the obvious potential of Therapeutic Drug Monitoring (TDM) as a tool to optimize psychopharmacotherapy, especially treatment with mood-stabilizing, antidepressant and antipsychotic drugs, acceptance of TDM as a routine tool is still limited. A serious scientific argument against the regular use of TDM is the lack of evidence for a concentration-dependent clinical effect. The aim of this review was to highlight methodological problems leading to poor or even negative concentration-effect relationships and to show how therapeutically effective concentrations of psychoactive drugs can be determined using routine TDM databases. Reports on concentration-effect relationships of psychoactive drugs were analyzed with regard to applied methods. From routine TDM databases of patients who had been treated with antidepressant or antipsychotic drugs and whose improvement was measured by the clinical global impressions scale, mean and median drug concentrations were calculated and compared with reference ranges recommended by TDM guidelines. Few fixed-dose studies with adequate design and data analysis demonstrated a correlation between drug concentration and clinical effect for psychoactive drugs. Most studies, however, mostly retrospective analyses of TDM databases, failed to find significant concentration-effect relationships because of flexible dosing. They were not suitable for the determination of therapeutically effective drug concentrations. Using TDM databases of antidepressant and antipsychotic drug concentrations in blood of patients who were categorized as responders by the clinical global impressions score, the interquartile ranges of drug concentrations (25th-75th percent range) can be shown to be very close to the therapeutic reference ranges recommended in guidelines for TDM in psychiatry. This review provides a discussion on why simple correlation analyses of psychoactive drug concentrations in blood and clinical effects are obsolete for flexible-dose studies or TDM databases. TDM databases, however, can and should be used to calculate drug concentrations in blood of patients who had responded to the drugs. Interquartile ranges can be regarded and used as preliminary therapeutic reference ranges.

Subchronic olanzapine exposure leads to increased expression of myelination-related genes in rat fronto-medial cortex

Schizophrenia is a psychotic disorder with severe and disabling symptoms, such as hallucinations, delusions, blunted affect and social withdrawal. The neuropathology remains elusive, but disturbances in immunity-related processes, neuronal connectivity and myelination have consistently been linked to schizophrenia. Antipsychotic drugs can be efficient in reducing symptoms, acting primarily on the dopamine system, but additional biological targets are likely to exist. Here we have screened for novel mechanisms of action in an animal model, using adult rats exposed to long-acting olanzapine, achieving stable and clinically relevant antipsychotic drug concentrations. By microarray-based examination of global gene expression in the fronto-medial cortex, at the single gene- and gene-set level, we observed downregulation of two neuropeptide-encoding genes, Vgf and Cort (fold change −1,25 and −1,48, respectively) in response to olanzapine exposure. Furthermore, we demonstrated significant upregulation of five out of ~2000 GO predefined gene sets after olanzapine exposure. Strikingly, all were linked to myelination and oligodendrocyte development; “Ensheathment of neurons”, “Axon ensheathment”, “Myelination”, “Myelin sheath” and “Oligodendrocyte development” (FDR-values < 25). Sixteen of the leading edge genes in these gene sets were analysed independently by qPCR, of which 11 genes displayed significant upregulation, including Plp1, Mal, Mag and Cnp (fold change: 1,30, 1,50, 1,30 and 1,15, respectively). Several of the upregulated genes (e.g. MAG, MAL and CNP) have previously been reported as downregulated in post-mortem brain samples from schizophrenia patients. Although caution needs to be taken when extrapolating results from animal studies to humans, the data suggest a role for olanzapine in alleviating myelination-related dysfunction in schizophrenia.

Recommendations for the monitoring of serum concentrations of antipsychotic drugs in the treatment of schizophrenia.

A 40-year-old man with schizophrenia is being treated with the longacting injectable form of risperidone. He comes to a community clinic for his second 50-mg dose since beginning treatment. His psychiatrist instructs him to stop concomitant use of oral risperidone 1 week after the second injection, as is recommended by the drug manufacturer. Three days following discontinuation of oral risperidone, the patient becomes fearful that his son, who lives with his ex-wife, has been kidnapped. He reaches this conclusion based on FBI and CIA radio transmissions that he believes he can hear being emitted from parked cars. He attempts to contact his family with this information and ultimately calls the police to his ex-wife’s home. When his family gets word of his decompensation, they bring him to the closest emergency room and he is admitted to an inpatient psychiatric facility. On admission, his combined serum level of risperidone and 9-OH-risperidone is found to be 10.4 ng/mL, approximately half the lower limit of the therapeutic range recommended by AGNP guidelines. Could evaluation of his serum level of risperidone prior to discontinuation of the oral medication have prevented this relapse and rehospitalization?

Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels.

In psychiatric clinical practice, there is a need to identify psychotropic drugs whose metabolisms are prone to be altered with increased inflammatory activity in an individual patient. The aim of this study was to find out whether elevated serum levels (≥5mg/l) of C-reactive protein (CRP), an established laboratory marker of infection and inflammation, are associated with increased serum concentrations of the atypical antipsychotic drugs clozapine, quetiapine, and risperidone. Therapeutic drug monitoring request forms of patients whose antipsychotic drug concentrations had been measured under conditions of normal (<5mg/l) and pathological (>5mg/l) levels of C-reactive protein were retrospectively screened. The serum concentrations in relation to the daily doses [concentration per dose (C/D) (ng/mL/mg)] and the metabolic ratios [ratio of concentrations (metabolite/drug)] were compared intraindividually by the Wilcoxon signed rank test. To the study effects of the intensity of infections on drug concentrations, C-reactive protein and C/D levels were submitted to Spearman's correlation analysis. Elevated levels of C-reactive protein were found in 105 patients. They were significantly associated with elevated values in C/D for clozapine (n = 33, P < 0.01) and risperidone (n = 40, P < 0.01). A trend for an increase was found for quetiapine (n = 32, P = 0.05). Median increases were 48.0% (clozapine), 11.9% (quetiapine), and 24.2% (active moiety of risperidone), respectively. In patients who exhibit signs of inflammation or infection with increased C-reactive protein values during psychopharmacological treatment, especially under clozapine and risperidone, therapeutic drug monitoring is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

P.3.d.049 Expected and effective plasma concentrations of antipsychotic drugs and attitude toward treatment

P.3.d.049 Expected and effective plasma concentrations of antipsychotic drugs and attitude toward treatment

Kjønns- og aldersforskjeller ved bruk av psykofarmaka

The dose recommendations in the Norwegian Pharmaceutical Product Compendium (Felleskatalogen) are not gender-specific, despite evidence of gender-dependent differences in the metabolism of a number of drugs. The purpose of this study was to investigate the extent to which age and gender influence the prescription and serum concentration of psychotropic drugs. The prescribed doses and serum concentrations of antidepressant, antipsychotic and antiepileptic drugs were studied in relation to age and gender in 1533 patients. Elderly women (≥ 65 years) were given somewhat lower doses of antidepressant drugs, but they had significantly higher serum concentrations than younger patients of either gender. Antidepressant drugs were prescribed in fairly high doses in the study population; the median number of defined daily doses was 1.5. The study suggests that when prescribing drugs, Norwegian physicians do not take sufficient account of the effect of age and gender on the pharmacokinetics of antidepressant drugs.

Table of Contents

AbstractDHA Supplements During Pregnancy for Postpartum Depression Not EffectiveDextromethorphan Plus Quinidine to Be Approved for Pseudobulbar AffectEffects of Duloxetine on Antipsychotic Drug ConcentrationsDHA Supplementation Fails to Slow DementiaFDA Proposes Plan to Reduce Opioid AbuseRisperidone LAI for Schizophrenia Relapse PreventionAntidepressant Efficacy for MDD and Comorbid Axis III DisordersResidual Effects of Zolpidem on Next‐Day DrivingRisperidone Long‐Acting Injection in Huntington's DiseaseNovember 2010 Safety Labeling ChangesNew Approvals

Clozapine Plasma Level Monitoring for Prediction of Rehospitalization Schizophrenic Outpatients

The aim of this naturalistic exploratory study was to examine whether blood antipsychotic drug concentrations can predict rehospitalizations in chronically medicated patients. The study included schizophrenic outpatients under clozapine (CLZ) maintenance treatment, supervised by therapeutic drug monitoring (TDM). Patients were observed for a period of 21 months. Their on average monthly measured plasma levels and the date of rehospitalizations were recorded. The variability of the first 3 CLZ plasma levels, measured in 3.6 months, was compared between patients with and without rehospitalization. 23 patients participated of which 6 patients were rehospitalized. Mean plasma concentrations of CLZ were similar in patients without (471 ± 180 ng/mL) and with rehospitalization (446 ± 266 ng/mL). However; coefficients of variation (CV) of plasma concentrations in the first 3 blood samples differed significantly between the rehospitalized and non-rehospitalized groups (37.1% vs. 13.0%, respectively, P = 0.012). A CV ≥ 19.8% was predictive for later rehospitalization with 100% sensitivity and 70.6% specificity. Variability in CLZ plasma concentrations may be useful in identifying patients at risk of relapsing under maintenance therapy. Because of the small number of patients the findings need to be confirmed in a larger study.

P-glycoprotein inhibition potentiates the behavioural and neurochemical actions of risperidone in rats

Antipsychotic drugs are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the metabolic pathways of antipsychotic drugs have been well defined, the role of drug transporters in the disposition and effects of antipsychotic drugs has not been systematically explored. P-glycoprotein has ubiquitous expression in brain endothelial cells and plays a protective role by effluxing substrates for elimination and by limiting their accumulation in the central nervous system. Risperidone and several other antipsychotic drugs are substrates of P-glycoprotein. Increased antipsychotic drug entry into the brain via blockade of the P-glycoprotein transporter may facilitate the amount of available drug to its targets, particularly dopamine receptors. By increasing available antipsychotic drug concentrations, P-glycoprotein inhibition offers a novel means of enhanced drug delivery. This study evaluated whether selective P-glycoprotein transporter inhibition would increase the effects of risperidone on relevant indices of behaviour (catalepsy and locomotion) and neurochemistry (dopamine release and metabolism as measured by in-vivo microdialysis). We administered the P-glycoprotein inhibitor, PSC 833 (100 mg/kg p.o.), to rats prior to administration of risperidone at varying doses (0.01-4.0 mg/kg s.c.). P-glycoprotein inhibition significantly increased risperidone-induced cataleptic effects, blockade of amphetamine-induced locomotion, and effects on dopamine turnover as seen by increased striatal dopamine metabolite levels. These results provide functional evidence concordant with prior data for increased brain levels of risperidone following PSC 833 treatment.

Impact of inflammation processes on blood serum levels of olanzapine, quetiapine and risperidone

Several case reports and a recently published study have reported that infections or inflammations can be associated with increased blood levels of clozapine. The aim of this study was to find out whether high serum concentrations of other atypical antipsychotic drugs are associated with elevated levels of C-reactive protein (CRP), a well established laboratory marker of infections and inflammations. CRP levels were analyzed in 41 patients treated with olanzapine, quetiapine or risperidone who exhibited serum concentrations above the therapeutically recommended target ranges. CRP levels were compared with those of 41 matched control patients with therapeutic levels of the antipsychotic drugs. Elevated drug levels were associated with higher mean levels of CRP in all three antipsychotic drugs, but the difference reached significance only for quetiapine (7.1±6.5 vs. 3.7±5.4mg/l, n=14; p=0.03), but not for olanzapine (13.5±29.5 vs. 10.1±26.2mg/l; n=17; p=0.63) or risperidone (13.9±7.2 vs. 6.9±7.2mg/l; n=10; p=0.20). It is concluded that in patients under treatment with antipsychotic drugs who exhibit signs of inflammation or infection, therapeutic drug monitoring (TDM) is recommendable in order to minimize the risk of intoxications due to elevated drug concentrations.

Antipsychotic Drug Levels in Psychiatric Primary Care Patients

Therapeutic Drug Monitoring (TDM) helps to maintain therapeutic drug levels for optimal therapeutic efficiency. It is routinely used in many psychiatric hospitals. By contrast TDM is rarely established in primary care patients. For outpatients TDM helps to avoid relapses or recurrence. In this study analysed the concentrations of antipsychotic drugs in schizophrenic outpatients of four different outpatient care units. Given that TDM gives rise to stable drug levels and thus to continuous stabilization of the patient's improvement it was expected that routine control of drug levels will reduce the risk of relapse.

Atypical Antipsychotics: Mechanism of Action

Atypical Antipsychotics: Mechanism of Action

Selective serotonin reuptake inhibitor augmentation in the treatment of negative symptoms of schizophrenia.

The treatment of negative symptoms of schizophrenia presents a major clinical challenge. This review examines the evidence pertaining to the efficacy, tolerability and safety of adding selective serotonin reuptake inhibitors (SSRIs) to antipsychotic agents in the treatment of negative symptoms in schizophrenia. Important methodological issues such as differentiating primary and secondary negative symptoms are discussed. The balance of available evidence indicates that at least some SSRIs, fluvoxamine and fluoxetine, can ameliorate primary negative symptoms in chronic schizophrenia patients who are treated with typical antipsychotics. The combination is safe and well tolerated although, as antipsychotic drug concentrations may be elevated, attention to dose and drug monitoring should be considered as appropriate. The effect of SSRI augmentation of atypical antipsychotics requires further study. Combination with clozapine may require particular caution because of potential toxicity if serum clozapine levels rise steeply. SSRI augmentation may be a useful addition to the treatment of schizophrenia.