Table 1.
Published case reports on late onset neutropenia/agranulocytosis with clozapine
| Author | Age (yr)/sex | Diagnosis | Dose of clozapine (mg/d) | Type of heamatological abnormality | Duration of clozapine use prior to neutropenia/agranulocytosis | Concomitant medications | Concomitant physical illness and clozapine associated complications | Remarks | Outcome |
|---|---|---|---|---|---|---|---|---|---|
| Voulgari et al.26) | 33/F | Schizoaffective disorder | 400 | TLC: 100 ANC: zero |
24 months | Levothyroxine 125 μg/d |
Streptococcus pneumonia Venous thromboembolism Allergic vasculitis |
G-CSF given | Rechallenge done No complication |
| Velayudhan and Kakkan17) | 44/F | Paranoid schizophrenia | 150 | TLC: 6,700→700 ANC: 4,690→<100 Over 7 days |
60 months | Risperidone 6 mg/d Trihexyphenidyl 4 mg/d |
Fever, rigor, swelling of right hand, sore throat, deep vein thrombosis right upper limb | Continued on risperidone 8 mg/d Chlorpromazine 150 mg/d Trihexyphenidyl 2 mg/d Partial remission |
Partial remission No rechallenge |
| Cohen and Monden5) | 42/M | Paranoid schizophrenia Opium abuse |
250 | Two months TLC: 2,500→1,900 ANC: 1,000→600 |
228 months | ±Lorazepam 2.5 mg/d | Fever, laryngitis | Aripiprazole 45 mg/d Lorazepam 5 mg/d Full remission |
Cell count recovery in one week No rechallenge |
| Raveendranathan et al.10) | 31/F | Paranoid schizophrenia | 325 | TLC: 2,820→2,200 ANC: 1,111→198 Over two weeks |
24 months (of rechallenge with 325 mg dose) | Risperidone 6 mg/d | Nil | History of neutropenia in past within 3 wks of clozapine dose 325 mg/d TLC: 10,100→6,500 ANC (details NA): rechallenge→2nd time agranulocytosis→risperidone 8 mg/d, HPL 30 mg/d, lithium 900 mg/d |
Rechallenge (after neutropenia) Treated with G-CSF (in 2nd episode), count normalised in 2 wks |
| Raja et al.9) | 65/M | Schizoaffective disorder | 450 | Over 7 months, progreesive neutropenia | 120 months | Metformin 500 mg/d | Nil | Risperidone 6 mg/d →olanzapine 10 mg/d+ quetiapine 150 mg/d | Cell count recovery in next week No rechallenge |
| Tourian and Margolese16) | 41/F | Paranoid schizophrenia Tobacco dependence |
100 | Three months (corresponding to increase in lamotrigine dose) | 84 months | Risperidone 1 mg/d Lamotrigine 100 mg/d |
Treated with stoppage of clozapine, lamotrigine; G-CSF + | Agranulocytosis associated with increase in lamotrigine dose | Rechallenge done No agranulocytosis |
| McKnight et al.35) | 33/F | Schizoaffective disorder | 96 | 300 | Details NA | Sodium valproate 1,500 mg/d Quetiapine 4,000 mg/d |
Nil | HLA – DQB1 testing done | Rechallenge Done No complication after rechallenge |
| Panesar et al.8) | 37/M | Schizoaffective disorder | 108 | Detail NA | TLC: 2,700 ANC: 500 |
Anti-tuberular medication | Nil | While on anti-tubercular drugs (duration detail NA) | Clozapine rechallenge 500 mg/d No complication after rechallenge |
| Ghaznavi et al.6) | 55/M | Paranoid schizophrenia | 168 | 750 | ANC: 2,556→1,620, over one month | Valproic acid 1,500 Donepezil (dose NA) |
Nil | Within one month of starting donepezil | Rechallenge in one week→clozapine increased 500 mg/d in 20 days; donepezil stopped, ANC 2,762→850 in 20 days, risperidone 6 mg/d |
| Manfredi and Sabbatani7) | 36/M | Severe depressive disorders Personality disturbances Suicidal behaviour |
NA | 16 weeks Severe leukopenia sudden onset (TLC: 1,050 ANC: 36 cells/μL) |
96 HPL | Lithium carbonate 600 mg/d Citalopram 40 mg/d Clomipramine 75 mg/d Lorazepam 2.5 mg/d |
Fever (pyrexia of unknown origin) | G-CSF | No rechallenge |
| Small et al.13) | 45/F | Schizophrenia Mild mental retardation Tobacco dependence |
72 | 500 | Sudden, 4,000→1,800, ANC: 2,000→198 | Olanzapine 10 mg/d HPL 150 mg/3 wk Benzopril hydrochloride 20 mg/d |
Nil | Clozapine rechallenge 800 mg/d, slow titration over 5 months Lithium added later→increase in TLC, ANC |
No complication after rechallenge |
| Thompson et al.15) | 34/M | Paranoid schizophrenia | 36 | 250 | ANC: 1,500/μL TLC: 5,840/μL |
Sod valproate 1,000 mg/d Sertraline 50 mg/d |
Nil | While on valproate, SSRI | No rechallenge |
| Bhanji et al.4) | 48/M | Undiff. schizophrenia | 550 | Fall in TLC (7,600→2,900) Drop in neutrophil count (3,000 →1,000) |
17 months (abrupt drop) | Risperidone 5 mg/d Olanzapine 15 mg/d Valproate 750 mg/d Quetiapine 50 mg/d |
Nil | Quetiapine associated with idiosyncratic leukopenic reactions - additive toxicity | Clozapine stopped→recovery in 8 days No rechallenge |
| Silvestrini et al.12) | 29/F | Undiff. schizophrenia | 300 | TLC: 2,600 ANC: 1,340/mm3 |
60 months | Clomipramine 75 mg/d | Insomnia, shivering, hot flushes, sense of tremor, symptoms of common cold, dry mouth | Thioridazine 350 mg/d olanzapine 20 mg/d, valproate 1,500 → more 2 months Clozapine rechallenge |
Cell count-recovery in 2 days Clozapine 500 mg/d Clomipramine 150 mg/d |
M, male; F, female; TLC, total leucocyte count; Nil, no comorbid physical illness; ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating factor; SSRI, selective serotonin reuptake inhibitors; HLA, human leukocyte antigen; NA, not available; Undiff., undifferentiated; HPL, haloperidol.