Introduction 1 The hypothermic effects of APDs seem less well known than the hyperthermic effects (e.g., malignant neuroleptic syndrome). Besides occasional case reports, little emphasis has been placed in scientific literature on hypothermia as adverse drug reaction (ADR). To our knowledge, a review of all reported and published cases of antipsychotic associated hypothermia has not yet been published. Methods The WHO international database for Adverse Drug Reactions was searched for reports of hypothermia and APD use (ATC-code N05A, with exclusion of lithium). The data in the database are collected from 77 countries participating in the WHO Program for International Drug Monitoring. This database comprises more than 3.5 million case reports, to which around 50,000 new reports are added quarterly. The relationship between the APD and hypothermia is evaluated by calculating the Reporting Odds Ratios (RORs) and 95% confidence intervals (95% CI) in a case/non-case design. The ROR compares the frequency of the reported ADR for a certain drug with the frequency of reports of that adverse drug reaction for all other drugs in the database. Reports concerning hypothermia were considered as cases, all other reports as non-cases. Index reports included all reports on an APD (ATC code beginning with N05A, with exclusion of lithium), all other reports were controls. When the number of reports of hypothermia in association with the APD is high and the number of reports of hypothermia in association with other drugs is low, ROR will be high. This also happens when the number of reports of other ADRs in association with the APD is low and the number of reports of other ADRs in association with other drugs is low. Since the vast majority of cases in the WHO database do not contain any details on indication of drug use, start and/or end dates and outcome, these factors cannot be analyzed with data from the WHO database. To get more information regarding characteristics of patients developing hypothermia during APD use, we performed a literature search in Medline and Embase for case reports with search terms “(antipsychotic OR neuroleptic) AND (hypothermia OR body temperature regulation), with no selection on date or language. From these articles, we searched the references for missing articles. Two reviewers judged all case reports. All relevant case reports were studied for patient, drug and environmental characteristics. Results 1 Table 1 Antipsychotic drugs and hypothermia: reports from the WHO database Antipsychotic drug Number of reports for hypothermia Number of reports for any ADR with this drug a Tioxanthenes  Zuclopenthixol 13 1094 15.88 (9.18–27.47)  Flupenthixol 6 1677 4.73 (2.12–10.55)  Chlorprothixen 4 502 10.58 (3.95–28.31)  Tiotixene 3 904 4.38 (1.41–13.62)  Clopenthixol 2 293 - Phenothiazines  Thioridazine 23 4436 6.90 (4.57–10.41)  Chlorpromazine 16 6182 3.43 (2.09–5.60)  Levomepromazine 11 2348 6.21 (3.43–11.24)  Cyamemazine 9 1197 9.99 (5.18–19.27)  Periciazine 8 430 25,00 (12.41–50.36)  Pipothiazine 3 197 20.36 (6.50–63.71)  Fluphenazine 3 2656 1.49 (0.48–4.62)  Trifluoperazine 3 1895 2.09 (0.67–6.48)  Perphenazine 2 1522 -  Prochlorperazine 2 4451 -  Promazine 2 307 -  Mesoridazine 1 215 - Butyrofenones  Haloperidol 32 10543 6.21 (3.43–11.24)  Pipamperone 10 546 24.62 (13.16–46.07)  Droperidol 2 1178 -  Benperidol 1 146 - Benzamides  Tiapride 5 596 11.14 (4.62–26.89)  Sulpiride 4 1828 2.89 (1.08–7.70)  Amisulpiride 1 1514 -  Sultopride 1 72 - Others  Loxapine 4 928 5.70 (2.13–15.23)  Pimozide 3 628 6.31 (2.03–19.65)  Zotepine 2 260 -  Prothipendyl 1 93 -  Penfluridol 1 58 - Atypical  Risperidone 129 18431 9.65 (8.09–11.52)  Clozapine 68 44255 2.05 (1.61–2.61)  Olanzapine 44 16090 3.65 (2.71–4.91)  Quetiapine 21 5374 5.19 (3.38–7.98)  Aripiprazole 11 4566 3.18 (1.76–5.76)  Ziprasidone 8 2963 3.57 (1.78–7.15) a 3 34 2 Table 2 Characteristics of cases with hypothermia following antipsychotic drug use in literature (43 case reports, 46 episodes) Characteristics Data Male 41% Age: mean (SD) 49 (23.0) Range 0–90 years Reported body temperature: mean (SD) 32,6°C (2.7) Range 20.0–36.1°C n Schizophrenia 51% Mental retardation 11%  Bipolar disorder 11% Dementia 11% Drug change Start or dose increase 80%  No change 16% Interval drug change detection hypothermia  <2 days 57%  2–7 days 16% Outcome death 4%  ICU admission 24% Hospitalization (incl. prolonged) 69% Discussion 3 35 36 37 38 39 40 41 41 42 43 2 The results of this study should alert physicians of the risk of hypothermia in psychiatric patients using APDs. There seems to be no direct relation between stable drug dose and the ADR; the period shortly after starting the APD or dose increase seems to be the high risk period. Often, drug changes are indicated by behavioral problems also leading to separation or isolation of the patient. In the case of separation, patients will be dressed lightly and, even at normal room temperature, can cool down easily. In these cases, the patient’s body temperature should be monitored daily (with a thermometer that can measure low body temperatures). Also, every change in behaviour or co-morbidity (e.g., infections) should be a warning sign to look for hypothermia.