Neuroleptic malignant syndrome (NMS) induced by second-generation antipsychotics is characterized by lower incidence, lower clinical severity, and less frequent lethal outcome than NMS induced by first-generation antipsychotics. |
Even the most recently marketed antipsychotics are not free from the risk of inducing NMS. |
Clozapine-, aripiprazole- and amisulpride-induced NMS can present with atypical features more frequently than other SGA-NMS, i.e. displaying less intense extrapyramidal symptoms or high fever. |
1 Introduction
2 Methods
2.1 Search Strategy
2.2 Inclusion and Exclusion Criteria
2.3 Data Extraction
2.4 Statistical Analysis
3 Results
3.1 Search Results
References | Sample | Study design and data sources | Treatment | NMS criteria; no. of cases and estimate of incidence | Deaths [n (%)] | Main findings and limitations |
---|---|---|---|---|---|---|
Biswasl et al. [14] | 1 Case of NMS; 8,858 subjects; 38 % F; mean age 43 ± 17 years; with SCZ, 39 %; PSY, 13 %; others 11 %; NS 33 % | Observational cohort study. Data on olanzapine prescriptions obtained from the NHS database through prescription-event monitoring method over a period of 2 years. Data on AEs collected through questionnaires sent to the GPs treating the subjects | OLA (100 %) | NS; 1/8.858 (0.056/1,000 × year) | None | Only one case of NMS reported, not lethal. EPS reported in 13 cases, more often among those aged 70 years and older than in younger subjects |
Chen et al. [19] | 50 Subjects with NMS; 44 % F; mean age 41 ± 14 years; with BD, 100 %. 800 controls without NMS matched for diagnosis, age, and date of BD insurgence | Case–control study. Data from medical claims database over a 5-year period. Cases with NMS identified from 154,474 subjects with BD, through spontaneous reports by treating physicians. | Cases: AP 34 %, of which 72 % were SGAs (OLA, 18 %; QUE, 28 %; RSP: 12 %; ZPR: 12 %; CLZ: 2 %); FGAs: 8 %; LIT: 10 %; BDZ: 16 %; APK: 8 %; AD: 30 % | ICD-9; 50/154.474 (0.064/1000*year)) | None | NMS was associated with the use of AP (aOR 2.4), male gender (aOR 2.1), confusion (aOR 2.9), dehydration (aOR 4.0), delirium (aOR 4.9), and EPS (aOR 3.5). Notably, only 34 % of NMS cases had been classified as currently receiving AP; authors commented that most AP treatment likely had not been registered (paid out-of-pocket by patients) |
Nakamura et al. [20] | 210 Cases with SGA-NMS; INPT, 100 %; 42 % F; with psychiatric diagnoses and neurological diagnoses; 210 controls with FGA-NMS matched by AP exposure | Case–control study. Data from administrative claims database (Japanese Diagnosis Procedure Combination) registering admissions to general hospi-tals over a period of 4 years (n = 12 million). Cases and controls were selected from 1,585 admissions for NMS | Cases: SGAs, 100 % Controls: FGAs, 100 % | ICD-10; NA | SGAs: 7 (3.3) FGAs: 16 (7.6) | Compared with FGA-NMS, SGA-NMS were associated with fewer admissions to ICU (21 vs. 31 %; p = 0.02) and with lower mortality (aOR 0,44; p = 0.08) after adjusting for gender, age, and CVD CVD was associated with increased NMS-related mortality |
Nielsen et al. [21] | 83 Subjects with NMS; 48 % F; mean age 51 years; with PSY, 48 %; ORG, 31 %; MD, 16 %; NEUR, 5 % 415 Controls matched by sex, age, and diagnosis; PSY, 48 %; ORG, 31 %; MD, 16 %; NEUR, 5 % | Retrospective and case–control study. Data from the DPCRR over a period of 12 years (224,000 subjects) Cases and controls were followed for 3 months before and after NMS diagnosis | Cases: SGAs, 37 %; FGAs, 69 % (high potency, 17 %; medium potency, 23 %; low potency, 28 %; depot, 13 %); BDZ, 65 %; LIT, 12 % Controls: SGAs, 19 %; FGAs, 27 % (high potency, 4 %; medium potency, 10 %; low potency, 13 %; depot, 6 %); BDZ, 32 %; LIT, 4 % | ICD-10; 83/224.372 (0.031/1000*year) | 7 (8.4) | In the general sample (n = 83), the risk of developing NMS was higher with lithium use (aOR 5.9; p < 0.05), depot (aOR 5.7; p = 0.005), SGAs (aOR 3.0; p < 0.01), benzodiazepine use (aOR 2.7; p < 0.005), and dose of AP (aOR 1.002; p < 0.05) In the group of patients treated with AP for 3 months before hospitalization (n = 62), the risk of developing NMS was higher with high-potency FGAs (aOR 23.4; p < 0.001), SGAs (aOR 4.7; p = 0.001), and depot AP (aOR 4.5; p < 0.005) Mortality within the first 30 days after NMS was higher among cases (HR 1.9; p < 0.01), especially females. Cases and controls were not matched by AP use, but for sex, age, and diagnosis |
Trollor et al. [11] | 165 Subjects with SGA-NMS; 27 % F; mean age 49 years; with PSY, 49 %; ORG, 2 %; MD, 3 %; ANX, 1 %; NS, 46 %. 43 controls with FGA-NMS; 30 % F; mean age 62 years; with PSY, 30 %; MD, 7 %; ORG, 2 %; other, 9 %; NS, 51 % | Retrospective study. Data from spontaneous NMS reporting in Australian ADRAC database over a period of 16 years Subjects in polytherapy were excluded (n = 85) | SGA-NMS: CLZ, 37 %; RSP, 16 %; OLA, 14 %; QUE, 7 %; AMI, 3 %; ARP, 2 %; PAL, 1 % | Delphi consensus; NA | SGAs: 3 %; FGAs: 16 % | Mortality rate in individuals with SGA-NMS was significantly lower than that of FGA-NMS, but the difference was reduced after adjusting for age. No other significant differences were found between the clinical presentation of SGA-NMS and that of FGA-NMS, except for clozapine-induced NMS that was characterized by a lower presence of rigidity and other EPS compared with other SGA-NMS |
Su et al. [22] | 67 Subjects with NMS; 36 % F; mean age 43 ± 18 years; with PSY, 46 %; BD, 27 %; SCZAFF,12 %; DEP, 4 %; others, 10 %; 254 controls matched (1:4) by age, gender, and diagnosis: PSY, 46 %; BD, 27 %; SCZAFF, 13; DEP, 5 %; others, 9 % | Case–control study. Data from the South London and Maudsley NHS Foundation Trust Case Register over a period of 9 years. At least one criteria for NMS diagnosis. Drugs were administered 5 (oral AP) or 15 (depot AP) days before the index date | 48 % SGAs only, 18 % FGAs only, 4 % ARP only, 45 % polytherapy, 10 % depot only | Levenson, Addonizio, Pope (definite or probable), Caroff, Adityanjee, DSM-IV | Deaths: NA | In univariate analyses, FGAs were associated with an OR of NMS of 3.9 (p < 0.001), whereas SGAs were not associated with significantly higher risk of NMS, with the exception of ARP (OR 2.5; p = 0.04). In multivariate analyses, compared with SGAs, the OR for NMS was significant for FGAs (2.81; p = 0.01), SGA/FGA associated (5.52; p < 0.001), but not for ARP (p = 2.43). Fluctuant doses and non-White ethnicity were also significant risk factors for NMS NMS case definition was based on fulfilling at least one of the six criteria set, resulting in a high degree of diagnostic heterogeneity. Only one case fulfilled all six criteria |
3.2 Case Report Analysis
OLA (n = 42) | QUE (n = 19) | RSP (n = 44) | ARP (n = 14) | CLZ (n = 36) | Missing [n (%)] | Statistics | |
---|---|---|---|---|---|---|---|
Gender [female; %] | 33.3 | 42.1 | 50 | 42.9 | 22.2 | – |
χ
2 = 7.18, df = 4, p = 0.13 |
Age [years; mean ± SD] | 46.2 ± 22.4 | 45.3 ± 18.8 | 39.6 ± 21.2 | 32.1 ± 18.2 | 39.9 ± 16.3 | – |
F = 1.68, df = 4, p = 0.16 |
Ethnicity [Caucasian; %] | 41.2 | 42.9 | 55 | 60 | 87.5 | 93 (60) |
χ
2 = 9.74, df = 12, p = 0.64c
|
Diagnosis [%] | 4 (2.6) |
χ
2 = 13.99, df = 12, p = 0.3 | |||||
Psychotic disorders | 52.5 | 44.4 | 50 | 71.4 | 77.1 | ||
Mood disorders | 25 | 27.8 | 25 | 21.4 | 17.1 | ||
Dementia | 15 | 15 | 9.1 | – | 2.9 | ||
Other | 7.5 | 7.5 | 15.9 | 7.1 | 2.9 | ||
Previous NMS [%] | 34.8 | 12.5 | 12.5 | 0 | 50 | 119 (76) |
χ
2 = 9.74, df = 4, p = 0.04*c
|
AP naive [%] | 26.7 | 15.4 | 41.2 | 38.5 | 4.0 | 40 (26) |
χ
2 = 12.15, df = 4, p = 0.02*,
c
|
Dose [mg; mean ± SD] | 12.1 ± 5.9 | 335 ± 270 | 3.7 ± 3.2 | 18.9 ± 9.2 | 332 ± 263 | 23 (15) | – |
CPZ eq [mean ± SD] | 253 ± 124 | 236 ± 190 | 279 ± 240 | 295 ± 144 | 308 ± 243 | 23 (15) |
F = 0.48, df = 4, p = 0.75 |
Dose increase [%]a
| 33.3 | 15.8 | 25 | 50 | 36.1 | – |
χ
2 = 5.71, df = 4, p = 0.22 |
Dose increase ≥50 [%]b
| 30.0 | 10.5 | 25 | 50 | 33.3 | – |
χ
2 = 6.87, df = 4, p = 0.14 |
Other treatments [%] | |||||||
SSRI | 11.9 | 10.5 | 11.4 | 7.1 | 2.8 | 31 (20) |
χ
2 = 2.54, df = 4, p = 0.64 |
Other AD | 4.8 | 5.3 | 6.8 | 0 | 2.8 | 31 (20) |
χ
2 = 1.49, df = 4, p = 0.83 |
LIT | 11.9 | 5.3 | 13.6 | 7.1 | 13.9 | 31 (20) |
χ
2 = 1.38, df = 4, p = 0.85 |
Other MS | 21.4 | 10.5 | 13.6 | 7.1 | 8.3 | 31 (20) |
χ
2 = 3.7, df = 4, p = 0.45 |
OLA (n = 42) | QUE (n = 19) | RSP (n = 44) | ARP (n = 14) | CLZ (n = 36) | Missing [n (%)] | Statistics | |
---|---|---|---|---|---|---|---|
Symptoms [%] | |||||||
Mental status change | 100 | 85.7 | 88.2 | 100 | 96.6 | 33 (21) |
χ
2 = 7.195, df = 4, p = 0.13 |
Rigidity | 91.4 | 92.3 | 94.1 | 100 | 67.6 | 27 (17) |
χ
2 = 15.472, df = 4, p < 0.01* |
Tremor | 92.3 | 100 | 91.7 | 81.8 | 44.4 | 107 (69) |
χ
2 = 10.596, df = 4, p = 0.03*d
|
Other EPS | 84.6 | 71.4 | 66.7 | 83.3 | 58.3 | 105 (68) |
χ
2 = 2.691, df = 4, p = 0.61d
|
Hyperpyrexia | 88.9 | 92.3 | 97.3 | 84.6 | 91.4 | 21 (14) |
χ
2 = 2.79, df = 4, p = 0.59 |
Temperature ≥38 °C | 79.4 | 78.9 | 94.3 | 58.3 | 79.2 | 31 (20) |
χ
2 = 13.386, df = 8, p = 0.10 |
Diaphoresis | 100 | 100 | 75 | 42.9 | 95 | 90 (58) |
χ
2 = 19.467, df = 4, p = 0.001*d
|
BP alteration | 88.2 | 90 | 73.7 | 76.9 | 81 | 58 (37) |
χ
2 = 2.499, df = 4, p = 0.64d
|
Tachycardia | 100 | 100 | 95.7 | 91.7 | 100 | 45 (29) |
χ
2 = 5.067, df = 4, p = 0.28d
|
Tachypnea | 70 | 100 | 70 | 60 | 100 | 113 (73) |
χ
2 = 5.163, df = 4, p = 0.27d
|
Dysphagia | 13.2 | 8.7 | 17.6 | 15.4 | 11.1 | 51 (27) |
χ
2 = 1.139, df = 4, p = 0.89d
|
Other autonomic symptoms | 14.3 | 15.8 | 25 | 35.7 | 25 | – |
χ
2 = 3.845, df = 4, p = 0.43 |
Laboratory tests | |||||||
CK elevation [%] | 97.4 | 91.7 | 97.1 | 92.3 | 85.2 | 18 (11) |
χ
2 = 4.885, df = 4, p = 0.30 |
CK [100 UI/l; mean ± SD] | 22.8 ± 55.0 | 29.1 ± 47.8 | 57.3 ± 15.5 | 24.8 ± 63.6 | 11.2 ± 41.9 | 33 (21) |
F = 1.347, df = 4, p = 0.33 |
CK peak [100 UI/l; mean ± SD] | 48.1 ± 65.5 | 54.8 ± 57.1 | 85.0 ± 178.9 | 35.9 ± 65.6 | 54.6 ± 121.7 | 33 (21) |
F = 0.569, df = 4, p = 0.69 |
Leukocytosis [%]a
| 80.0 | 80 | 70.8 | 70.0 | 75 | 54 (35) |
χ
2 = 0.824, df = 4, p = 0.94d
|
WBC [1,000 U/l; mean ± SD] | 14.3 ± 7.6 | 11.9 ± 4.8 | 15.3 ± 5.2 | 15.5 ± 5.4 | 13.9 ± 6.0 | 78 (50) |
F = 0.443, df = 4, p = 0.78d
|
Symptom duration [days; mean ± SD] | 8 ± 5.4 | 13.7 ± 8.4 | 9.7 ± 9.8 | 7.5 ± 3.0 | 10.4 ± 9.9 | 65 (42) |
F = 1.174, df = 4, p = 0.33d
|
NMS severity [points; mean ± SD]b
| 35.3 ± 8.3 | 31.1 ± 8 | 36.3 ± 8.3 | 31.6 ± 10.1 | 28.8 ± 8.3 | 57 (36) |
F = 3.3, df = 4, p = 0.01*d
|
Timing of NMS symptomsc
| |||||||
Mental status change | 1.0 | 0.5 | 1.5 | 0.8 | 1.0 | 57 (36) |
F = 0.319, df = 4, p = 0.86d
|
Rigidity | 1.2 | 0.3 | 1.5 | 1.1 | −1.2 | 48 (30) |
F = 1.163, df = 4, p = 0.33d
|
Tremor | 1 | 0.7 | 1.7 | 1.1 | 0.0 | 115 (74) |
F = 0.183, df = 4, p = 0.94d
|
Other EPS | 1.9 | 0.3 | 3.4 | 1.6 | 2.0 | – |
F = 0.040, df = 4, p = 0.99 |
Diaphoresis | 0.7 | 0.8 | −0.1 | 0.0 | 1.4 | 103 (66) |
F = 0.212, df = 4, p = 0.93d
|
Hyperpyrexia | 0.7 | 0.1 | 0.7 | −2.2 | 2.2 | 43 (27) |
F = 1.363, df = 4, p = 0.25d
|
Tachycardia | −0.4 | 0.3 | −0.2 | −3.3 | 1.4 | 61 (39) |
F = 1.992, df = 4, p = 0.10d
|
Tachypnea | −1.1 | 0.2 | −0.5 | 0.0 | −0.5 | 113 (72) |
F = 0.373, df = 4, p = 0.83d
|
BP alteration | −0.1 | 0.1 | −0.1 | 0.2 | 0.4 | 74 (47) |
F = 0.282, df = 4, p = 0.89d
|
Other autonomic disorders | 5.3 | 0.0 | 2.7 | 0.0 | 3.0 | – |
F = 0.539, df = 4, p = 0.71 |
CK | −0.7 | 0.0 | 0.0 | −3.6 | −0.4 | 42 (27) |
F = 1.939, df = 4, p = 0.11d
|
Leukocytosis | 0.5 | −0.1 | 0.0 | 0.0 | −0.6 | 69 (44) |
F = 0.861, df = 4, p = 0.49d
|
OLA (n = 42) | QUE (n = 19) | RSP (n = 44) | ARP (n = 14) | CLZ (n = 36) | Missing [n (%)] | Statistics | |
---|---|---|---|---|---|---|---|
NMS treatment [%] | |||||||
ICU and intubation | 35.7 | 30.0 | 24.2 | 38.5 | 29.2 | 47 (30) |
χ
2 = 1.38, df = 4, p = 0.85a
|
Any antiparkinsonian | 34.4 | 40 | 59.0 | 53.8 | 27.6 | 27 (17) |
χ
2 = 8.52, df = 4, p = 0.07 |
Dopaminergic | 30.3 | 40 | 53.8 | 38.5 | 27.6 | 26 (17) |
χ
2 = 6.27, df = 4, p = 0.18 |
Anticholinergic | 3.1 | 6.7 | 10.3 | 23.1 | 3.4 | 27 (17) |
χ
2 = 6.30, df = 4, p = 0.18 |
Myorelaxants | 51.5 | 86.7 | 48.7 | 61.5 | 51.3 | 26 (17) |
χ
2 = 7.21, df = 4, p = 0.13 |
Outcome [%] | |||||||
Complete recovery | 75 | 61.5 | 87.9 | 81.8 | 80 | 50 (32) |
χ
2 = 4.32, df = 4, p = 0.37a
|
Death | 6.5 | 7.7 | 2.9 | 0 | 7.1 | 36 (23) |
χ
2 = 1.64, df = 4, p = 0.81 |
AMI (n = 7) | PAL (n = 4) | ZPR (n = 6) | ZOT (n = 4) | Missing [n (%)] | |
---|---|---|---|---|---|
Gender, female | 28.6 | 50 | 66.7 | 25 | – |
Age [years; mean ± SD] | 47.6 ± 18.9 | 39.5 ± 24.7 | 35 ± 16.1 | 52.5 ± 13.6 | – |
Ethnicity [Caucasian; %] | 33.3 | 100 | – | 40 | 18 (60) |
Diagnosis [%] | |||||
Psychotic disorders | 42.9 | 75 | 66.7 | 100 | |
Mood disorders | 28.6 | – | 33.3 | – | |
Dementia | 28.6 | – | – | – | |
Other | – | 25 | – | – | |
Mean dose [mean ± SD]a
| 480 ± 179 | 7.5 ± 1.7 | 86.7 ± 46.8 | 325 ± 247 | 8 (26.7) |
Symptoms [%] | |||||
Mental status change | 100 | 100 | 100 | 100 | 2 (6.7) |
Rigidity | 83.3 | 100 | 80 | 100 | 5 (16.7) |
Diaphoresis | 75 | 100 | 100 | 100 | 12 (38.7) |
Hyperpyrexia | 71.4 | 100 | 100 | 100 | 3 (10) |
Temperature ≥38 °C | 50 | 50 | 50 | 66.7 | 4 (13.3) |
Tachycardia | 80 | 100 | 100 | 100 | 10 (33.3) |
Tachypnea | – | – | 33 | – | 24 (80) |
BP alteration | 83.3 | 75 | 83.3 | – | 7 (23.3) |
Other autonomic symptoms | 100 | 25 | 33.3 | – | – |
Tremor | – | 100 | 100 | 50 | 17 (56.7) |
Other EPS | – | 100 | 100 | – | 23 (76.7) |
Laboratory tests | |||||
CK [100 UI/l; mean ± SD] | 77.9 ± 62.9 | 74.2 ± 129 | 319 ± 437 | 21.3 ± 37.3 | – |
CK peak [100 UI/l; mean ± SD] | 79.5 ± 61.5 | 76.7 ± 128 | 382 ± 475 | 392 ± 392 | 3 (10) |
Leukocytosis [%] | 80 | 50 | 80 | 100 | 10 (33.3) |
WBC [1,000 U/l; mean ± SD] | 16.6 ± 4.8 | 16.2 | 20 ± 9.4 | 15.3 ± 2.9 | 15 (50) |
Symptom duration [days; mean ± SD] | 10.5 ± 5.8 | 14.2 ± 5.7 | 10.4 ± 1.5 | 15.0 ± 1.5 | 12 (40) |
Outcome [%] | |||||
Complete recovery | 80 | 100 | 75 | 100 | 10 (33.3) |
Death | 20 | – | – | – | 7 (23.3) |