Table 5.
Metabolic and endocrine adverse effects in relation to clozapine plasma levels.
| Reference | Type of Study | Age (Mean) (Years) | Comedication | Averaged Serum Levels of Clozapine (ng/mL) | Duration | Reported Side Effects |
Correlation to Clozapine Plasma Levels | Jadad Score |
|---|---|---|---|---|---|---|---|---|
| [63] | Prospective, double-blind, randomized | 44.8 ± 9.6 | No | CLOZ: >350 in responders | 29.7 ± 13.2 weeks (16 weeks, 32 weeks, 48 weeks, based on response status) | Weight gain | In nonsmokers (n = 8) r = 0.89 (p = 0.046) | 2 |
| [81] | Prospective, observational, open-label | 37.4 ± 9.3, (range 22–57) | Not reported | 500 ± 280 (range 70–1360) | 32.6 ± 6.6 weeks (23–62 weeks) | Weight gain, waist circumference | No (r = −0.04, p = 0.77) at follow-up |
0 |
| [65] | Cross-sectional | 38.2 ± 11.3 (range 22–74); Caucasians: 40.2 ± 8.6, Asians: 36.3 ± 13.4 | Not reported | Caucasians: 415.3 ± 185.8 Asians: 417.1 ± 290.8 |
≥6 months | Lipid profiles, fasting glucose levels | No | 0 |
| [70] | Cross-sectional | 46 (29–63) | Not reported | Median: 359.1 (range 60.5–810.46) | At least 6 months Median: 5.3 years (range 0.5–16.3 years) |
Fasting insulin, C-peptide, insulin-like growth factor I, insulin-like growth factor binding protein-1, leptin, glucose and lipids | CLOZ vs. insulin: r = 0.51, p = 0.03 CLOZ vs. C-peptide: r = 0.48, p = 0.04 CLOZ vs. triglycerides: r = 0.50, p = 0.03) |
0 |
| [49] | Cross-sectional | 35 (26–47) | No | 28.8–721 | 2.7 (range 0.5–7.3 years) | Fasting glucose, insulin, growth hormone (GH)-dependent insulin-like growth factor I (IGF-I), and insulin-dependent insulin-like growth factor binding protein-1 | CLOZ vs. insulin levels | 0 |
| [50] | Open, prospective | Males: 34.7 ± 8.1 Females: 36.2 ± 11.6 |
Benztropine (n = 6), diphenylhydantoin (n = 2), fluoxetine (n = 1), divalproate (n = 1) | 6 weeks: 388 ± 242 6 months: 444 ± 355 |
6 months | Weight gain | No | 0 |
| [51] | Cross-sectional | 36.5 ± 11.3 | Antipsychotics (61.9%), antidepressants (14.3%), mood stabilizers (21.4%) | CLOZ: 1613.57 ± 976.05 NCLOZ: 964.60 ± 976.05 |
Stable clozapine therapy for at least 6 months | Metabolic syndrome BMI |
CLOZ vs. metabolic syndrome | 0 |
| [74] | Retrospective | Males: 36.9 (95% CI: 33.9–39.8) Females: 39 (95% CI: 35.4–42.7) |
Aripiprazole (n = 6) Amisulpride (n = 4) Haloperidol (n = 2) For the females: estrogen-containing contraceptive pill (n = 5), estrogen-containing hormone replacement treatment |
CLOZ: Males: 440 (10th–90th percentile: 260–700) Females: 490 (10th–90th percentile: 270–790) NCLOZ: Males: 310 (10th–90th percentile: 260–350) Females: 310 (10th–90th percentile: 270–340 |
Males: 4.4 (95% CI: 1.2–10.3) years Females: 5.1 (95% CI: 2.3–7.9) years |
BMI Fasting blood glucose HDL |
CLOZ vs. BMI CLOZ vs. fasting blood glucose |
0 |
| [45] | Cross-sectional | Median: 41 (range: 29–36) | Benzodiazepines (n = 4), and/or levomepromazine (n = 3) and/or lithium (n = 1) | CLOZ: 392(69–918) NCLOZ: 288 (88–641) |
6.9 years (range: 0.7–16.3 years) | Elevated blood glucose, elevated levels of insulin, elevated levels of C-peptide, elevated triglycerides, cholesterol, HOMA-IR | CLOZ vs. insulin: r = 0.53, p = 0.03, CLOZ vs. C-peptide r = 0.51, p = 0.04 CLOZ vs. triglyceride levels: r = 0.46, p = 0.06 |
0 |
| [71] | Prospective, randomized | Coadministration group: 32.9 ± 8.5 Monotherapy group: 35.1 ± 9.4 |
No | Coadministration group: CLOZ: 509.8 ± 281.1 NCLOZ: 179.0 ± 95.8 Monotherapy group: CLOZ: 502.0 ± 220.6 NCLOZ: 242.8 ± 100.3 |
12 weeks | Serum glucose, cholesterol, and TRG levels, weight gain |
NCLOZ vs. weight gain: r = 0.27, p = 0.026 NCLOZ vs. blood sugar: r = 0.34, p = 0.005 NCLOZ vs. Triglycerides: r = 0.27, p = 0.028 |
2 |
| [77] | Cross-sectional, controlled | Patients: 40.94 ± 10.15 Controls: 40.09 ± 1.67 |
Not reported | CLOZ: 594.90 ± 492.90 NCLOZ: 220.33 ± 182.55 |
At least 4 months | Blood measures | CLOZ vs. total cholesterol: r = 0.34, p = 0.04 | 0 |
| [41] | Cross-sectional | 36.6 ± 9.1 (range 20–54) | Benzodiazepines, lithium, antidepressants, other medically indicated agents | CLOZ: mean = 297 (median: 291), among 68 samples. Subsample not exposed to fluoxetine or valproate (n = 27): 239 ± 159 |
2.15 ± 2.30 years | Excess weight | No | 0 |
| [66] | Double-blind dose–response | 49 females (32–60 years old), 42 males (31–58 years old) | No | 400–1600 | 16-week | Hyperprolactinemia | For every 100 ng/mL increase in plasma clozapine levels, average increments in prolactin levels of 0.45 ng/mL in females and 0.15 ng/mL in males were recorded | 2 |
| [75] | Cross-sectional | 42.5 (20–65) | CLOZ Monotherapy: 65.4%, CLOZ + atypical: 22.5%, CLOZ + typical: 9.7%, CLOZ +typical + atypical: 1.7% |
Men (722 ± 366) and women (886 ± 480) | 3–12 months (1.7%), 1–5 years (32.5%). 5 years (57.8%), unspecified (8%) |
Menstrual problems | No correlation with CLOZ + NCLOZ concentration | 1 |
| [77] | Cross-sectional, controlled | Patients: 40.94 ± 10.15 Controls: 40.09 ± 1.67 |
Not reported | 594.90 ± 492.90 220.33 ± 182.55 |
At least 4 months | Blood measures | No correlation with TSH, FT4, PRL. CLOZ vs. FT3: r = −0.373, p = 0.021 |
0 |