Abstract
Prolongation of clozapine-induced neutropenia with olanzapine
Olanzapine could be associated with haematological abnormalities [1, 2]. Six reports suggest prolongation or recurrence of clozapine-induced leucopenia and neutropenia with olanzapine [3–8]. Given unavailability of local data, we wish to share such a clinical presentation.
A 32-year-old woman was commenced on clozapine in October 2003 for treatment-resistant schizophrenia. She was stabilized with clozapine 250 mg day−1 and had normal haematological profile until recently (May 2006), when she developed a sudden drop in white blood cell (WBC) count (3.4×109 L−1) and neutrophils (1.0×109 L−1). Following haematologist consultation, her clozapine was discontinued because there were no other etiological explanations for this abnormality. Simultaneously, she was commenced on olanzapine 20 mg day−1 to prevent psychotic relapse and to minimize clozapine withdrawal side-effects (day 1). Due to persisting neutropenia (0.9–1.2×109 L−1) and fluctuating WBC count (3.3–4.1×109 L−1), on day 8, olanzapine was discontinued, and aripiprazole 15 mg day−1 commenced. Her neutrophil count returned to normal (2.3×109 L−1) within 2 days (on day 10) and remained stable, with improvement in WBC count (4.4–4.6×109 L−1).
Two reports reveal prolonged granulocytopenia when olanzapine was commenced in the presence of leucopenia and granulocytopenia [5, 8]. While haematological normalcy occurred within 1 week following olanzapine discontinuation in one report [5], olanzapine was continued despite leucopenia due to improved mental state in another [8]. In the present patient there was persistence of neutropenia and fluctuation of total white cell count with olanzapine treatment, but haematological normalcy was noted within 2 days of olanzapine discontinuation.
Putative mechanisms for olanzapine-induced haematological abnormalities include a toxic or immune-mediated mechanism, genetic determinants, bioconversion into reactive nitrenium ion, impaired granulocyte-colony stimulating factor secretion, interaction with bone marrow extracellular matrix components, dose-dependent adversity and cross-sensitivity [1, 2]. Also, olanzapine could be granulocytotoxic when added immediately following clozapine-induced granulocytopenia and could reduce the clearance of clozapine, thereby prolonging its effect on granulocytes [5].
On a pragmatic level, this report raises concerns about the haematological safety profile of olanzapine during the phase immediately following discontinuation of clozapine for haematological reasons.
Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine
Patients with co-morbid depression and pain disorder are common in clinical practice [1] and could in many instances be treated with a combination of antidepressants and analgesics that act synergistically on the serotonin system, such as selective serotonin re-uptake inhibitors (SSRIs) and tramadol. Serotonin syndrome (SS), which could be conceptualized as the most severe form of the spectrum of serotonin toxicity, is characterized by cognitive behavioural changes (agitation, confusion, and hypomania), neuromuscular excitability (myoclonus, hyperreflexia, tremor, and incoordination) and autonomic nervous system dysfunction (diaphoresis, shivering, diarrhoea, alteration in blood pressure and temperature) [9–11]. Drugs that increase the concentration of serotonin in the synaptic cleft or modulate the serotonergic system, could theoretically enhance the vulnerability for SS [1, 2]. Typically the onset of symptoms are abrupt, with 75% of cases developing within 24 h of medication changes [9–11].
Grouped data from controlled studies suggest that SSRIs as a class have minimal risk to cause manic switching compared to placebo, particularly in unipolar depression and even in bipolar depression [4]. We report a case of abrupt onset of SS and manic switch in a patient suffering from unipolar depression, who was maintained on a stable dosage of 20 mg paroxetine and 200 mg tramadol, temporarily associated with sudden increase of these medications.
A 53-year-old woman was brought to the emergency department (ED) of Armadale-Kelmscott Hospital, by her daughter, with a history of acute onset of agitation, arousal, disorganized behaviour and two episodes of witnessed generalized tonic–clonic seizure. She had been on treatment for depression, arthritis, type II diabetes (well controlled with diet) for several months through her general practitioner and had been stable on paroxetine 20 mg, alprazolam 0.5 mg and tramadol 200 mg daily. Due to worsening of pain, she reported increasing the dosage of paroxetine and tramadol up to 4 tablets a day prior to the onset of the aforementioned symptoms. She was not on any antipsychotic medications and there was no history of substance abuse, infection, head injury, or past history of mania, psychosis or epilepsy. Examination over the next few days revealed confusion, agitation, slurred and pressured speech, elated and labile affect, grandiose delusions, poor insight and neurological signs of myoclonic jerks of facial muscle, ankle clonus and increased muscle tone. Other findings observed intermittently included tachycardia, mild increase in temperature (up to 38oC), increase in blood pressure and dilated pupil. All the aforementioned symptoms (except symptoms of mania) subsided over a period of 1 week. By this time manic symptoms were florid and they took 8 weeks to remit on sodium valproate 2 g and olanzapine 20 mg. Computed tomography of the head was normal. Creatinine kinase was only slightly high. Other investigations did not reveal evidence of metabolic or infectious aetiology.
The aforementioned clinical picture is suggestive of the co-occurrence of both SS and mania. The rapid onset of symptoms, presence of clonus, absence of exposure to antipsychotics and temporal association with increase in serotonergic drugs suggest that her condition was likely to be due to SS, rather than neuroleptic malignant syndrome [9–11]. The presence of symptoms from the dimensions of cognitive behavioural changes, autonomic dysfunction and neuromuscular symptoms and seizures again points to a diagnosis of SS in the present patient [1, 2].
Tramadol is a unique analgesic that acts on multiple sites and inhibits the re-uptake of serotonin and noradrenaline in a dose-dependent manner [5]. The sudden increase in dosage of tramadol in combination with paroxetine, both endowed with strong serotonin re-uptake inhibition, could have possibly triggered SS in this patient. It is unclear whether pre-existing diabetes and arthritis could have increased the vulnerability for SS by causing damage to vascular endothelium [2]. Although hypomanic symptoms do occur in SS, the persistence of severe manic state after the remission of other symptoms of SS, necessitating inpatient treatment for a considerable period, warrants independent diagnosis of mania. We speculate that the sudden increase in the dosage of paroxetine and tramadol created a hyperserotonergic state, which could have caused the manic switch. The pharmacodynamic interaction between paroxetine and tramadol could have been possibly enhanced by a pharmacokinetic interaction. Paroxetine is a potent inhibitor of CYP2D6 and this could possibly increase the blood level of tramadol several fold [5]. Thus both pharmacodynamic and pharmacokinetic mechanisms could be relevant in the genesis of SS and manic switch in this patient.
The present case report indicates the need for careful monitoring of side-effects and mental state in patients prescribed combinations of drugs acting synergistically on the serotonin system.
Amantadine in acute bipolar mania
Amantadine was originally introduced into pharmacotherapy as an antiviral drug to treat acute influenza A virus infection. Recently amantadine was also shown to be highly efficacious in depression associated with Borna disease virus (BDV) infection [14–16]. Correlative evidence of clinical diagnosis with laboratory findings monitoring BDV infection was and still is complicated by debates on the significance of infection markers [4].
Against this hindrance to clinical research, we report here on three (European Caucasian) bipolar I disorder patients during acute non-psychotic mania (DSM-IV-criteria) who tested BDV positive via EIA methods [4]. All rapidly improved following an amantadine augmentation (100 mg b.i.d., morning and midday) without experiencing relevant side effects.
Mrs A, a 46-year-old female grammar school teacher, single, has been suffering from a bipolar disorder for 17 years. Despite prophylactic treatment with valproate (1800 mg day−1), she suffered from a pure manic exacerbation after having a dispute with her employer. During hospitalization, manic symptoms measured on the Young Mania Rating Scale (YMRS) scored 33. During valproate and amantadine co-medication manic symptoms decreased to 2 (YMRS) within 18 days.
Mr B, a 55-year-old unemployed man, was diagnosed to have bipolar disorder at the age of 39. Hospital admission was necessary resulting from an acute manic exacerbation with sleeplessness, logorrhoea and euphoria. On admission, his YMRS score was 21. Following amantadine augmentation added to the basic medication of lamotrigine (150 mg day−1), oxcarbazepine (450 mg day−1) and diazepam (10 mg day−1) the manic symptoms rapidly improved. After 12 days his YMRS score dropped to 7.
Ms C, aged 62, has been known to suffer from a rapid-cycling bipolar disorder for at least 8 years. Previous long-term treatment strategies led to only partial improvement. Also the latest combination therapy (oxcarbazepine 450 mg day−1, lamotrigine 150 mg day−1, levothyroxine 150 mg day−1) did not prevent the current manic episode rated 20 (YMRS), which required hospital admission. After augmentation with amantadine her YMRS score dropped to 9 within 6 days.
These moderately manic patients showed a remarkable improvement with amantadine augmentation documented by the YMRS scores (22–33 vs 2–8). One patient (Mr B.) had already been successfully treated with amantadine 4 years earlier during a depressive episode. In contrast to what could be expected in manic patients due to amantadine's pharmacology, no adverse effects such as psychotic symptoms or restlessness occurred, in line with parallel observations in Austria [3]. The present findings not only point to a clear benefit and safety of amantadine in mania, but also appear to support a contribution of a possible BDV infection in mania as seen in depression [1, 2, 4]. Prospective, double-blind and placebo-controlled trials are necessary to confirm clinical and virological data.
Lamotrigine-induced manic switches have already been reported
Dr Desarkar and Dr Sinha described a lamotigine-induced severe manic switch in the latest issue of the journal [1] but this is not the only, nor the first case, in the literature [2]. Readers of this journal remember the lamotrigine study from Turkey in which two bipolar depressive patients switched to manic phase under lamotrigine [2]. The authors commented that those manic switches may have challenged the drug's putative mood stabilizing role [2]. Dr Desarkar and Dr Sinha carried out a meticulous search of the literature until February 2006 and therefore the reported cases from Turkey should be regarded as additional information. Lamotrigine's probable propensity to cause manic switch should be borne in mind, as the per these reports [1, 2].