Table 4.
Cardiovascular adverse effects in relation to CLOZAPINE blood levels.
| Reference | Type of Study | Age (Mean) | Comedication | Averaged Serum Levels of Clozapine (ng/mL) | Duration | Reported Side Effects | Correlation to Clozapine Plasma Level | Jadad Score |
|---|---|---|---|---|---|---|---|---|
| [35] | Cross-sectional | 37.6 ± 1.67 | Levomepromazine or chlorprothixene. Other medication as usual | Median S-CLOZ: 351 (231–615) (range: 64–1824) | 2.5 (1.0–9.0) years | Increased pulse rate (>80 bpm), tachycardia (>100 bpm), orthostatic hypotension |
No | 0 |
| [39] | Prospective, randomized, double-blind | 38 (range 21–56) | Haloperidol, phluphenazine, valproate | Low: 91 ± 15 (50–150), medium: 251 ± 13 (200–300), high: 396 ± 16 (350–450) | 12 weeks | Tachycardia: Orthostaic hypotension: | No | 2 |
| [40] | Prospective, longitudinal, observational, partly double-blind (n = 22) partly open-label (n = 32) | Range: 8–18 | No | Week 6: CLOZ 455 ± 285.1, NCLOZ 302.4 ± 142.2 | 6 week treatment at first and then 2–6 years follow-up | Hypertension (>140/90 mmHg), orthostatic hypotension, tachycardia (>120 bpm) |
No | 0 |
| [42] | Prospective, non-randomized, double-blind, observational | 37.61 ± 8.68 (range 21–63) | Chloral hydrate. Lorazepam. Valproate |
Week 6: Clozapine: 470.20 ± 234.23, range 100–1220 Norclozapine: 233.06 ± 105.56, range 70–670, Week 12: clozapine 681 ± 390.71 ng/mL (range 220–1920 ng/mL), NCLOZ 297.8 ± 146.49 ng/mL (range 8–720 ng/mL) |
12 weeks | QTc alterations | No | 0 |
| [44] | Prospective, open-label | Not reported | Not reported | 200–300 ng/mL (divided into three groups I: <30 ng/mL, II: 30–100 ng/mL, III: >100 ng/mL for paranoid-hallucinatory schizophrenic patients and manic syndrome) | 30 days | Orthostatic hypontension, temperature | Yes, with severity of orthostatic dysregulation | 0 |
| [43] | Open-label | 13.3 ± 2.7 (range 9–16) | No | Crude (ng/mL): 289 ± 116, Normalized (ng/mL-mg-Kg): 99 ± 37.3 | 6 weeks | Tachycardia | No | 0 |
| [64] | Prospective longitudinal | Not reported | Lorazepam allowed | Mean serum CLOZ level by week (1–8): 63.5 ± 46.0 199.3 ± 149.1 251.9 ± 178.0 300.7 ± 200.2 316.2 ± 189.4 364.7 ± 195.6 351.9 ± 176.2 379.5 ± 156.5 | First 8 weeks of administration | Hypotension, temperature, pulse | The blood pressure and pulse did not change significantly from baseline to week 8. Temperature was inversely related to clozapine dose (p < 0.003) Higher norclozapine to clozapine ratios were associated with higher BP measures (p = 0.002). The magnitude of these relationships is weak (r < 0.30). There is a tendency to autonomic dysregulation during clozapine use |
0 |
| [80] | Cohort, prospective study, open | 44 ± 12 | Not reported | 475 ± 236 | Mean follow-up of 9 ± 6 years | Myocarditis, sudden death | No | 0 |
| [79] | Retrospective, review of case records | 31.21 ± 9.59 | None: 52.44% Antidepressants: 19.51% Mood stabilizers:31.71% Stimulants: 1.22% |
CLOZ: 305.56 ± 299.64, nor CLZ: 160.23 ± 105.12 | 18 weeks | - | No | 1 |
| [76] | Preliminary prospective study | 35.5 ± 11.0 | One other antipsychotic, one mood-stabilizing drug, or a benzodiazepine | CLOZ: 124 ± 70.8 nor CLOZ: 52.3 ± 35.7 | 4 weeks | Increased Heart Rate, Myocardial Performance Index (MPI) > 0.44. Reduced LV functioning |
No | 0 |
| [72] | Cross-sectional | Patients: 40.7 (range: 21–68) Controls: 41.2 (range: 20–64) |
No | 290 | >8 weeks | HRV | Yes, negative (inverse) correlation | 0 |
| [73] | Retrospective | 42.1 (range: 19–73) | Haloperidol, benzodiazepines, SSRIs, Carbamazepine | 331 ± 294 (range: 65–1475) | >1 week | HRV | Yes, negative (inverse) correlation | 0 |
| [48] | Cross-sectional | 33.5 (range: 26–41) | Not reported | 451 (range: 337–569) (n = 29) | 7 (range: 3–13) | Persistent tachycardia | No | 0 |
HRV: Heart Rate Variability.