Received date: February 05, 2016; Accepted date: February 25, 2016; Published date: March 04, 2016
Clozapine is an atypical antipsychotic used in the management of treatment-resistant schizophrenia. Numerous clinical trials, including randomized double-blind clinical trials and large cohort studies, have revealed that clozapine is more effective than any other antipsychotic drugs. It is has been around since the 1960s and was withdrawn from use after an association with neutropenia (incidence 3%) and agranulocytosis (0.8%) was made. The pivotal study by Kane et al. in the 1980s proved that clozapine was more effective than conventional antipsychotics and it was reintroduced in the UK with compulsory haematological monitoring [1,2].
Studies have shown that 30% of patients who have previously been refractory to treatment improve significantly after 6 weeks’ treatment with clozapine and up to 60% respond after one year. Although claims are made for the efficacy of clozapine in negative symptomatology, clinical gains in this area are much less marked. Clozapine treatment reduces suicidality and the data are sufficient for specific labeling for this indication in the USA. Clozapine has also a unique side-effect profile in that it has been associated with an extremely low incidence of extrapyramidal side-effects (EPSEs) and is not to cause precipitate tardive dysckinesia (TD). Many of the adverse effects of clozapine are dose-dependent and associated with speed titration  (Tables 1 and 2). However, the same studies have also shown that this drug has several adverse gastrointestinal effects such as acute necrotizing enterocolitis (ANE). Commonly the clozapine cause gastrointestinal hypo motility and Ogilvie syndrome (acute pseudo-obstruction caused by a disturbed balance in the autonomic regulation of intestinal motility) is described after clozapine usage [4,5].
|Adverse effect||Time course|
|Sedation||First few months.|
|May persist, but usually wears off|
|Hypersalivation||First few months.|
|May persist but usually wears off.|
|Often very troublesome at night.|
|Hypotension||First 4 week|
|Hypertension||First 4 week|
|Tachycardia||First 4week,but sometimes persists|
|Weight gain||Usually during the first year of treatment|
|Fever||First 3 weeks|
|Seizures||May occur at any time|
|Nausea||First 6 weeks|
|Nocturnal enuresis||May occur at any time|
|Neutropenia/agranulocytosis||First 18 weeks (but may occur at any time)|
Table 1: Clozapine – common adverse effects.
|Agranulocytosis/neutropenia||Occasional reports of apparent clozapine-related blood dyscrasia even after 1year of treatment|
|Delirium||Reported to be fairly common, but rarely seen in practice if dose is titrated slowly and plasma level determinations are used|
|Eosinophilia||Reasonably common but significance unclear. Some suggestion that eosinophilia predicts neutropenia but this is disputed. May be associated with colitis and related symptoms|
|Heat stroke||Occasional case reported.May be mistaken for (Neuroleptic malignant syndrome (NMS).|
|Hepatic failure/enzyme abnormalities||Benign changes inLFTs are common (up to 50%of patients) but worth monitoring because of the very small risk of fulminant hepatic failure.|
|Rash may be associated with clozapine-related hepatitis.|
|Pancreatitis||Rare reports of asymptomatic and symptomatic pancreatitis sometime associated with eosinophilia.|
|Some authors recommend monitoring serum amylase.|
|Pneumonia||Very rarely results from saliva aspiration.|
|Infections in general may be more common in those on clozapine.|
|Note that respiratory infections may give rise to elevated clozapine levels. (Possible an artifact:smoking usually ceases during an infection).|
|Thrombocytopenia||Few data but apparently fairly common.|
|Probably transient and clinically unimportant.|
|Vasculitis||One report in the literature in which patient developed confluent erythematous rash on lower limbs.|
Table 2: Clozapine – uncommon or unusual adverse effects reported since its relaunch in 1990.
The occurrence of seizures appears to be dose-related and can be managed by reduction in clozapine dosage. Clozapine-induced necrotizing colitis has been described in the literature and the anticholinergic activity is believed to the cause. Intestinal necrosis is a partial or total necrosis of the small or large bowel with a mucosal starting point and consecutively transmural progression. Current pathophysiological of necrotizing enterocolitis can be related to three possible mechanisms:
a) Small intestine obstruction leading to distension, necrosis, perforation or sespsis . The condition that increased intraluminal pressure reduces perfusion and causing ischaemia. Colonic distension may result in perforation, especially if the small intestine diameter exceeds 12 cm. The mortality rate for pseudo-obstruction may be as high as 50% if it progresses to ischemic necrosis and perforation.
b) Aspiration from inhalation of feculent vomitus or dysphagia;
c) Fecal stasis leading to translocation of luminal bacteria across the epithelial barrier, triggering an exaggerated and damaging local inflammatory response. The initial symptomatology, less than 24 hours, is represented by functional digestive signs such as abdominal pain, vomiting, nausea with or without emesis, diarrhea.
The aim of this study was to reviewer retrospectively all cases of ischaemic colitis and intestinal necrosis related to clozapine required an urgent surgical treatment registered in the Pharmacovigilance Database up to January 1997 to day.
We searched in the pharmacovigilance database all cases of ischaemic colitis and gastrointestinal necrosis related to clozapine between 1997 and December 2014. We analyzed retrospectively all clozapine case reports of ischemic colitis and gastrointestinal necrosis underwent to surgical procedure and all case reports of several digestive complications clozapine-related resolved with conservative treatment (Table 3) [7-18]. A literature search was performed using the databases PubMed (1950-2014), EMBASE (1980-2014), and Scopus, MEDLINE, EMBASE and SCOPUS were searching using the term such as: ischemic colitis, colon ischemia, bowel ischemia, intestinal necrosis, colon perforation, bowel perforation, clozapine.
|Author||Nb cases||Medical and Psychiatric History||Clinical Presentation||Surgical Treatment andOutcome|
|Levin et al. ||1||chronic paranoid schizophrenia of 20 years’ duration||abdominal pain||died before surgery|
|Townsend et al. ||1||long history of schizophrenia||abdominal pain + vomiting||died before surgery for bowel ischaemia(post-mortem examination)|
|Leong et al. ||1||chronic schizophrenia||abdominal distension+ vomiting and diarrhea||right hemicolectomy without primaryanastomosis|
|Peyrièreet al.||38||schizophrenia in 14 ptanother psychosis in 6 pt
bipolar disorder in 3pt
mental retardation in 3pt severe depression in 1 pt autism in 2pt delirium in 1pt psychopathic personality in 1pt
|abdominal pain + vomitingdiarrhea||partial or total resectionof the colon and/orsmall bowel in 24 pt(9pt suffered from ischaemic colitis and 15 from necrotizing colitis)|
|Hibbard et al. ||2||schizophrenia||Constipation, tender abdomen,Hypotension and tachycardia||died for bowel necrosis before surgery|
|McKinnon et al. ||1||history of treatment-resistant schizoaffective disorder urinary incontinence with a permanent cystostomy||Abdominal pain + feculent vomiting||subtotal colectomy with intraoperative ileorectalanastomosis|
|Laviet al.||1||schizophrenia of 40 years’ duration||Tender abdomen + nausea + constipation||cecotomy and transverse colostomy|
|Hasan B. Alamet al.||1||Paranoid schizophrenia||Abdominal distension and shock||recovered with conservative treatment|
|Prietoet al. ||1||schizophrenia||nausea + constipation||no surgery|
|Fayadet al. ||1||schizophrenia||abdominal pain+ vomiting||died before surgery(autopsy was not performed)|
|Park et al. ||1||Bipolar disorder + depression||abdominal pain||no surgery|
|Ikaiet al. ||1||schizophrenia||abdominal distension + shock||laparotomy for perforation of large intestine|
|Shah et al. ||1||chronic schizophrenia||constipation, abdominal pain,vomiting||colonic resection with stomaFormation|
|SCet al.||1||chronic schizophrenia||nausea; abdominal pain||died before surgery 1 week after taking clozapine|
Table 3: Summary of Case Reports Published of ischaemic colitis and gastrointestinal necrosis clozapine related.
The clozapine has been shown to have a better efficacy and side-effects profile over other typical and atypical antipsychotic drug. The risk of causing agranulocytosis is well established and estimated to be 1%, a reason responsible for its initial withdrawal from the market before its reintroduction. Several case studies have shown various life-threatening side effects of clozapine, ranging from haematological (agranulocytosis), cardiac (cardiomyopathies, pericarditis), nervous (seizure), metabolic (diabetes, dyslipidaemia, liver failure) and gastrointestinal complications [19-21]. A review of the mortality effect of clozapine showed that it lowers the mortality rate in severe schizophrenia by decreasing suicide rates, while the mortality rate for less common causes of death, such as pulmonary embolism and cardiac failure is higher . Reported gastrointestinal side effects of clozapine are oesophagitis, constipation and bowel ischemia [23,24]. Constipation is a very common complication occurring in 14% to 60% of patients [25-34]. Less well recognized is clozapine’s potential to impair motility throughout the gastrointestinal system causing dysfagia, ileus, intestinal obstruction, bowel ischemia and megacolon.
The possible mechanisms by which clozapine cause ischemic colitis and gastrointestinal necrosis are reported by Palmer et al. . They hypothesize three possible mechanism can have a fatal outcome: The first possible mechanism is an untreated bowel obstruction or pseudo obstruction leading to distension, necrosis, perforation or sepsis. Colonic distension may result in perforation especially if the bowel diameter exceeds 12 cm. The mortality rate for pseudo-obstruction may be as high as 50% if it progresses to ischemic necrosis and perforation . The second possible mechanism is the aspiration from inhalation of feculent vomitus or dysphagia and finally another possible mechanism is represented by the fecal stasis leading to infection. Peyriére et al. reported that 24 out of 36 patients treated with clozapine were undergone to surgical operation, 9 patients from ischemic colitis and 15 from necrotizing colitis . The mortality rate among the patients who underwent surgery was 25% (6 patients died).
In the analysis of 102 cases Palmer et al., 28 patients died (27.5%), 42 recovered (41.2%) and in 32 cases (31.4%) the outcome was unknown . The large number of death may indicate difficult or delayed diagnosis or rapid decompensation. It is very important for clinicians to know that these symptoms may be these of an ischemic colitis or gastrointestinal necrosis related to the treatment of psychiatric disease. In the literature the population was young, 47% of the whole population and 64% of the death being under 40 years-old. Risk factors for digestive complications in these young patients were infection HIV related, enteritis, obesity and gastrointestinal infection and metabolic disorders. Nausea tends to develop later in the course of treatment and affects 11% of patients. The pathophysiological basis is uncertain but may involve the anticholinergic effect of delayed gastric emptying. Constipation occur in 1 percent of patients treated with clozapine and can be severe.
Three deaths from severe ileus and obstipation have been reported [29-34] (Table 4). It is most likely due to the anticholinergic properties of clozapine and other medications with anticholinergic properties may exacerbate it. Because long term use of stimulant cathartics can result in degenerative changes in colonic muscles and nerves, short-term treatment is recommended. So, constipation in psychotic patient should be monitored because the risk for ischemic colitis is higher in patient with constipation . The biological data is very poor in review of literature, nevertheless in the literature metabolic acidosis is considered as a factor of seriousness and early metabolic acidosis should incite the clinicians to be aware for visceral intestinal complications (ischaemic or infectious). Three cases of gastrointestinal necrosis were reported in patients treated by clozapine [35-37].
|M, 29||Aspiration of vomit secondary to obstruction of the transverse colon||Hayes and Gibler |
|F, 31||Large bowel obstruction with mucosal necrosis, pulmonary edema, and shock||Thèret et al.|
|M, 49||Intermittent indigestion, nausea, chest pain, and vomiting. Collapsed with pulmonary edema secondary to inhalation of feculent vomit||Drew and Herdson |
|M, 36||Necrotizing colitis||Shammi and Remington |
|M, 43||History of ulcerative esophagitis. Abdominal pain, feculent vomiting, and severe fecal impaction with large intestinal necrosis||Levin et al. |
|M, 44||Found dead. Evidence of pulmonary edema, paralytic ileus, and gastroenteritis||Ferslew et al.|
|F, 47||Large bowel infarct||Flanagan et al.|
Table 4: Death due to clozapine associated gastrointestinal hypomotility.
A recent publication reports one case of acute necrotizing enterocolitis (ENA) induced by antipsychotics (quietapine), were reported in the literature one case of neonatal delayed peristalsis after in-utero exposure to clozapine.
The mechanism for this syndrome probably is related to the anticholinergic effect of the clozapine associated with a substantial plasmatic concentration and possible increased half-life elimination. Finally we hypothesize that the high mortality rate related to severity of ischaemic colitis induced by clozapine in schizophrenic patient can be associated to altered sensitivity to pain and it can be responsible of delayed diagnosis and treatment.
The physicians should be suspicious when abdominal digestives symptoms are present with-out evidence of other predisposing factors and in future a multidisciplinary approach (psychiatrists, surgeons and radiologist) towards the overall management of this complication and is key factor for a good outcome because an early diagnosis and early surgery can improve the chances of these patients.