Complications
Hyperammonaemic encephalopathy has been reported following initiation of valproate semisodium therapy in patients with urea cycle disorders. Prior to initiating valproate semisodium, consider evaluation for urea cycle disorders in the following patients: 1) a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postnatal encephalopathy, unexplained intellectual disability, or history of elevated plasma ammonia or glutamine; 2) cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low urea, or protein avoidance; 3) family history of urea cycle disorders or unexplained infant deaths (particularly males); 4) other signs or symptoms of urea cycle disorders.[291]
The rate of lamotrigine-induced rash of benign variety in patients with mood disorders has been reported to be 8.3%, compared with 6.4% with placebo treatment.[293] Serious rash rate was 0.1% among lamotrigine-treated patients across all controlled and open-label trials. Rash risk is likely to be related to starting dose and rate of titration, so prevention of rash is best accomplished by following established dosing guidelines for a slow, gradual up-titration. Early discontinuation of lamotrigine may prevent progression to Stevens-Johnson syndrome. Do not re-challenge patients with a history of a serious lamotrigine rash.[294]
The incidence of metabolic syndrome in bipolar disorder is 30%.[77] Atypical antipsychotics have been associated with weight gain, induction of type 2 diabetes, and dyslipidaemias. The risk seems greatest with olanzapine and clozapine, intermediate with quetiapine and risperidone, and low for aripiprazole and ziprasidone.[284] Prevention of this complication is best achieved by choosing lower-risk agents first and carefully monitoring fasting blood glucose, weight, blood pressure, abdominal circumference, and fasting lipids before and during treatment with any atypical antipsychotic. The aetiology for atypical antipsychotic-induced metabolic derangements is unknown.
The incidence of cognitive dysfunction in patients with bipolar disorder is not known, and is complicated by state and trait variables. For example, impaired concentration or distractibility is common during a state of active mood disturbance. However, studies have demonstrated several deficits in neuropsychological function in patients with bipolar disorder during well periods, suggesting trait abnormalities.[278] Deficits in attention, executive function, and emotional processing have been reported to persist during euthymic states in bipolar disorder.[279] Neuropsychological testing may aid in the detection of this complication, although prevention and treatment strategies have not been established.
Weight gain is a common adverse effect associated with many medications used to treat bipolar disorder. The incidence of this complication varies based on individual patient factors, specific medication, and treatment duration. Among the agents approved to treat bipolar disorder, only lamotrigine, carbamazepine, aripiprazole, lurasidone, cariprazine, and ziprasidone are associated with a low risk for weight gain. About 54% of patients with bipolar disorder are overweight, and 31% meet criteria for obesity.[77] Medications are likely to contribute to this complication. Monitor weight at baseline and throughout treatment. Encourage healthy eating and regular exercise.
Lithium-induced nephrogenic diabetes insipidus is a frequent complication, with 30% to 80% of patients having some degree of difficulty in concentrating the urine. Polyuria, nocturia, and thirst are symptomatic. Diabetes insipidus is caused by inhibition of vasopressin-stimulated adenylate cyclase and reduced density of vasopressin receptors in the collecting tubules. Using the lowest effective dose of lithium may reduce the risk of developing diabetes insipidus.[288]
Chronic lithium nephropathy and nephrotic syndrome are rare complications of lithium therapy.[289]
The prevalence of hypothyroidism in lithium-treated patients is between 6.0% and 39.6%. Lithium-induced hypothyroidism is thought to be related to an autoimmune process, or by direct action of lithium on hormone secretion leading to goitre. Monitor thyroid function tests every 6-12 months.[290]
The results of one large systematic review and meta-analysis (containing more than 4 million participants) suggest that patients with bipolar disorder have a significantly raised risk of developing idiopathic Parkinson's disease compared with the general population (odds ratio 3.35).[295] The authors highlight the need to consider the possibility of Parkinson's disease in patients with bipolar disorder and parkinsonism, regardless of concomitant medication.
US data report up to 50% of all people with bipolar disorder have been estimated to make at least one suicide attempt in their lifetime, with 10% to 15% of people with bipolar disorder dying by suicide.[31][32][33] The highest rates of suicidality occur during the acutely depressed phase of bipolar disorder, with the majority of the suicidal attempts or deaths occuring during the depressive phase.[34][35][36] Comorbid panic disorder has been reported to increase the risk of suicidal behaviour and indicate a more severe course.[8] Suicide risk is higher earlier in the course of the illness, with estimates at around 25%.[274] The aetiology of suicide is unknown, although it is likely that a confluence of variables including social factors, psychological traits, neurobiological influences, and genetics merge to convert suicidal thoughts into action. Many risk factors for suicide have been reported, but their common denominator may simply be human suffering.[275] Suicide is preventable. Be familiar with suicide risk assessment and development of an intervention plan.[275] Start acute intervention immediately.[276] Long-term treatment with lithium is effective in preventing suicide and attempted suicide in patients with unipolar and bipolar depression.[189][276][277] Other factors that may contribute to a good outcome for suicidal patients include the establishment of a multidisciplinary treatment team, family involvement, social support, and a safe and secure environment.[276]
Adults with bipolar disorder are 40% less likely to be employed and 7 times more likely to miss work.[280][281] During periods of mania or severe depression, individuals with bipolar disorder may clearly be unable to perform the activities of daily living, particularly if hospitalisation becomes necessary. Another contributing factor is that, despite the availability of effective treatments, most people with bipolar disorder do not receive adequate care. Early detection and aggressive treatment may reduce disability.
Signs and symptoms of lithium toxicity usually emerge at blood levels >1.5 mEq/L, although toxicity may be observed at much lower concentrations in some patients. Intentional overdose, drug interactions, recent increase in dose, a decrease in renal excretion, and recent medical illness, especially if marked by excessive fluid loss, are all potential causes of lithium toxicity. The signs and symptoms of this complication include neurological (fine tremor, gait abnormality, hyperreflexia), gastrointestinal (nausea, vomiting, diarrhoea), and cardiovascular (bradycardia, T-wave changes, conduction blocks). With increasing levels of lithium (2.5 to 3.5 mEq/L), slurring of speech, myoclonus, and a coarsening of the tremor may occur. Lithium blood levels >3.5 mEq/L are life-threatening, as renal failure, stupor, seizures, and cardiovascular collapse are likely.[286]
Neurotoxic effects of lithium from case reports include extrapyramidal side effects, cognitive dysfunction, peripheral neuropathy, nystagmus, and pseudotumour cerebri. Pre-existing cerebral abnormalities, advanced age, and concomitant use of antipsychotics and tricyclic antidepressants may increase the risk for this complication. Lithium initiation and chronic administration commonly cause a fine tremor of the upper extremities that is a postural and/or action tremor of high frequency; approximately 20% prevalence for lithium-induced tremor has been reported. Using the lowest effective dose of lithium may reduce or eliminate the tremor. In some cases, low doses of propranolol can be used to treat the tremor.[287]
At recommended therapeutic doses for bipolar disorder, atypical antipsychotics are associated with a very low risk for acute EPS phenomena such as dystonic reactions and akathisia. Risperidone may have a greater risk for causing EPS and hyperprolactinaemia than other atypical antipsychotics; aripiprazole is associated with akathisia. Although as a class of medications the atypicals carry a lower risk for EPS than the typical antipsychotics, case reports exist for all the atypicals linked to EPS and to tardive dyskinesia. Selective serotonin-reuptake inhibitors (e.g., citalopram) and lithium have also occasionally been implicated.[285] Consider the severity of the extrapyramidal symptoms and of the underlying disorder when deciding on a treatment approach, and on whether to stop or switch medication.
Hepatic failure resulting in fatalities has occurred as a rare complication of valproate semisodium therapy, usually during the first 6 months of treatment. Serious or fatal hepatotoxicity may be heralded by malaise, weakness, lethargy, facial oedema, anorexia, and vomiting. Monitor patients closely for appearance of these symptoms. Perform liver function tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months.[291]
Life-threatening pancreatitis has been reported as a complication of valproate semisodium therapy. Some cases have been haemorrhagic, with rapid progression from initial symptoms to death. Onset of pancreatitis is variable; some occur shortly after initiation of valproate semisodium, and others after several years of use. In clinical trials, there were 2 cases of pancreatitis without alternative aetiology in 2416 patients, representing 1044 patient-years of experience. The emergence of abdominal pain, nausea, vomiting, and/or anorexia should prompt medical evaluation.[291]
Aplastic anaemia and agranulocytosis have been reported as rare complications of carbamazepine therapy. The risk of their occurrence is 5 to 8 times greater than that observed in the general population. Transient or persistent decreased platelet or white blood cell counts have also been observed. Monitor blood cell count before and during treatment, and increase the frequency of monitoring should any downward trend in white blood cells or platelets emerge.[292]
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