Table 3.
Nervous system and psychiatric adverse effects in relation to CLOZ 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 |
|---|---|---|---|---|---|---|---|---|
| [34] | Prospective, randomized | 38 (range: 21–56) | Rarely given doses of haloperidol or fluphenazine | group I (n = 16): 50–150 group II (n = 22): 200–300 group III (n = 12): 350–450 |
12 weeks |
Seizures, EEG changes, sleepiness | EEG abnormalities, more severe than borderline, rate: group III: 73% vs. group I: (20%) and group II: 21% (p = 0.006) Severity: group I 0.9 ± 1.8, group II 1.0 ± 1.5, group III 3.4 ± 1.9 (p < 0.001) Spike/sharp activity: no correlation Slowing: more slowing in group III vs. group II and I (p = 0.049), positive correlation with levels (r = 0.44, p = 0.002), possible cutoff: 300 ng/mL Sleepiness: positive correlation with levels (r = 0.33, p = 0.029). The EEG slowing correlated with observed sleepiness |
2 |
| [58] | Prospective, observational | 31.7 ± 10.2 | No | Whole sample (n = 29): 161.3 ± 150.0 group 1 (n = 14): 81.6 ± 64.6, group 2 (n = 15): 235.7 ± 169.8 | 20.2 ± 16.8 days | EEG changes | Plasma levels significantly different among groups according to severity of EEG changes. Group 1 (n = 14): degree 0–1, plasma levels: 81.6 ± 64.6 ng/mL (95% CI = 44.3–118.9). Group 2 (n = 15): degree 2–4, plasma levels: 235.7 ± 169.8 mg.mL (95% CI: 141.7–329.7) (p = 0.0009) |
0 |
| [35] | Cross-sectional, blinded for EEG measures | 37.6 ± 1.67 |
Levomepromazine or chlorprothixene for sedation up to 100 mg/day. Other medication as usual | Median CLOZ: 351 (231–615) (range: 64–1824) | 2.5 (1.0–9.0) years | EEG changes | Severity correlated to plasma CLOZ (r = 0.43; p < 0.05) but not NCLOZ levels. CLOZ concentrations ≥1306 ng/mL lead to progressive gradual EEG changes |
0 |
| [39] | Prospective, randomized, double-blind | 3 (range 21–56) |
All psychoactive medication tapered off. Valproate in two patients with a history of seizures | Low: 91 ± 15 (50–150), medium: 251 ± 13 (200–300), high: 396 ± 16 (350–450) | 12 weeks | Sleepiness, EPS |
Trend of sleepiness and serum level to correlate at week 6 (p = 0.08), but no significance at week 12. EPS improved over time, with no group-by-time interactions. |
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 + CLOZ 302.4 ± 142.2 |
6 week treatment at first and then 2–6 years follow-up | EEG changes seizures, akathisia |
Rates of side effects were not directly associated with CLOZ or nor CLOZ blood levels or their ratio | 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 | Sedation | No | 0 |
| [42] | Prospective, non-randomized, double-blind, observational | 37.61 ± 8.68 (range 21–63) | Chloral hydrate, Lorazepam, Valproate |
Week 6: cloz: 470.20 ± 234.2, range 100–1220 norclozapine: 233.06 ± 105.56, range 70–670, Week 12: cloz 681 ± 390.71, range 220–1920, NCLOZ: 297.8 ± 146.49 range 8–720 |
12 weeks | EEG changes, akathisia, EPS | No significant correlation between plasma levels and EEG abnormalities on week 6, BARS, AIMS, SAS scores on weeks 6 and 12, negative correlation with sedation at week 6, which was clinically implausible | 0 |
| [47] | Retrospective, observational | 37.7 ± 11.7 | Valproate (n = 25, 35.2%) Mood stabilizers (lamotrigine, valproate, lithium, topiramate) (n = 31) Antipsychotics, antidepressants, benzodiazepines, or mood stabilizers in combination (n = 68) |
CLOZ: 429.4 ± 264.1 NCLOZ: 197.8 ± 132.6 |
4.6 ± 4.9 years | EEG changes | Positive correlation with CLOZ levels (p = 0.008). No correlation with NCLOZ levels (p = 0.12). Patients with CLOZ levels > 600 ng/mL had higher rate of EEG abnormalities (93.8%) than those with levels <600 ng/mL (65.5%) (p = 0.02) |
0 |
| [75] | Cross-sectional | Age: 42.5 (range: 20–65) | Clozapine monotherapy: 65.4%, CLOZ + atypical: 22.5%, ClOZ + typical: 9.7%, CLOZ + typical + atypical: 1.7% |
Men: 722 ± 366, Women: 886 ± 480 (p = 0.03) Total sample: 778 ± 444.57 |
3–12 months (1.7%), 1–5 years (32.5%), 5 years (57.8%), not specified (8%) |
Difficulty in concentrating, tension, difficulty remembering things, depression, restlessness, difficulty getting to sleep | Yes, only with the Depression/Anxiety score | 0 |
| [68] | Single-blind, cross-sectional | Group I: 45 ± 10.3, Group II 47.2 ± 7.5 |
No | Group I: CLOZ ≥300 Group II: CLOZ <300 |
≥5 years | Cognitive performance | No relationship between clozapine plasma levels and cognitive performance. Tendency to significance regarding the executive test (31% of variability of number of attempts in the WCST was explained by clozapine plasma levels) | 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 | Sedation | No | 0 |
| [59] | Retrospective analysis of clinically collected cross-sectional data. | 41.6 ± 12.0 | Not reported | All subjects (n = 73): 458.5 ± 248.8 Low cognitive impairment (n = 57): 437.1 ± 249.6 High cognitive impairment (n = 16): 534.7 ± 237.7 | ≥3 months | Cognitive impairment | Sixteen subjects (21.9%) had high cognitive impairment and the rest had low cognitive impairment. Age and clozapine levels were associated with high cognitive impairment, as well as clozapine/desmethylclozapine raitio (OR: 7.3). Yes | 0 |
| [56] | Cross-sectional | 39.3 ± 8.8 | Mood stabilizer (31%), Anticholinergic (18%), antidepressant (16%) other antipsychotic (5%), anxiolytic or hypnotic (5%) | CLOZ: 530 ± 370, NCLOZ: 310 ± 190 |
Median (range): 30 (3–156) months | Memory and concentration problems, night-time sleep problems, Parkinsonism, akathisia, tardive dyskinesia |
No correlation | 1 |
| [62] | Double-blind, prospective. Randomized to clozapine doses |
Not reported | Haloperidol | End of first trial (16 weeks): 335 ± 340 | First trial: 16 weeks, second trial:16 weeks | Drowsiness, sedation | Clozapine levels were very good predictors of serum antimuscarinic activity in doses of 300 mg/d or higher. Sedation showed no significant association with serum antimuscarinic activity. | 2 |
| [60] | Retrospective, naturalistic, 1-year study/cross-sectional | 37.9 ± 9.3 | Fluvoxamine (n = 8), fluoxetine (n = 2), sertraline (n = 2), paroxetine (n = 1), valproate (n = 15) | Patients with OCS: 595.1 ± 364.9 (range 84–1491) Patients without OCS: 433.5 ± 252.8 (range 82–1273) |
Patients with OCS: 81.8 ± 32.2 months, Patients without OCS: 56.1 ± 40.6 months | OCS | Plasma concentration of clozapine was significantly higher in patients with OCS than in those without (p = 0.001) | 0 |
CLOZ: clozapine, NCLOZ: norclozapine, OCS: obsessive-compulsive symptoms.