Complications
In newer studies of children taking lamotrigine for seizure disorder, the rate of serious rash was quite low. The risk of a rash developing is likely related to starting dose and rate of titration, so prevention is best accomplished by following established dosing guidelines. Early discontinuation of lamotrigine may prevent progression to Stevens-Johnson syndrome. Patients with a history of serious rash should not be rechallenged with lamotrigine.[229]
Weight gain is an unfortunately common adverse effect with the majority of medications used to treat bipolar disorder. The incidence of this complication varies based on individual patient factors, specific medication, and duration of treatment. Medications are likely to contribute to this complication.
Of the approved second-generation antipsychotics, olanzapine is the most likely to cause weight gain, and aripiprazole the least.[148]
Careful monitoring of weight at baseline and throughout medication management is necessary. Healthy eating and exercise habits should be encouraged, particularly because there is some evidence that young people with bipolar disorder are less likely than their peers to achieve the recommended benchmark for regularly working out.[225][226]
With regard to medication management of weight gain, although metformin appears to be superior to other agents when compared with placebo, the evidence is too limited to support regular use.[227]
The prevalence of hypothyroidism in lithium-treated patients depends on their age and how long they have been taking it. The etiology of lithium-induced hypothyroidism is thought to be related to an autoimmune process, or to the direct action of lithium on hormone secretion, leading to goiter.
Prevention through routine monitoring of thyroid function tests every 6 to 12 months is recommended. Should hypothyroidism occur, thyroid hormone replacement is the appropriate treatment if lithium needs to be continued.[225]
One Danish population study has reported that, at age 15 years, remaining life expectancy before age 90 years was decreased by 12.7 and 8.9 life-years for men and women with bipolar disorder, respectively. This was largely attributable to natural causes, suggesting that early intervention in bipolar disorder also needs to focus on decreasing the risk of comorbid general medical illnesses.[5]
Second-generation antipsychotics have been associated with weight gain, induction of type 2 diabetes mellitus, and dyslipidemias. The risk appears greatest with olanzapine and clozapine, intermediate with quetiapine and risperidone, and low for aripiprazole and ziprasidone (consensus statement).
Prevention of this complication is best achieved by a combination of choosing lower-risk agents first and careful monitoring of fasting blood glucose, weight, blood pressure, abdominal circumference, and fasting lipids before and during treatment with any second-generation antipsychotic. The etiology for second-generation antipsychotic-induced metabolic derangements is unknown.[225]
With regard to the second-generation antipsychotics, treatment with risperidone is associated with the greatest risk for hyperprolactinemia followed by olanzapine; aripiprazole is associated with reduced prolactin levels.[148]
Developmental progress in executive functions and verbal memory was significantly poorer in one study comparing bipolar patients with nonbipolar controls. Over time, improvement on attention, working memory, visual memory, and visuospatial perception tasks were comparable in both groups, but the patients with bipolar disorder remained impaired in all domains relative to the controls.[221][222] In another study, processing speed and visual-motor skills normalized during follow-up in a treated group of young people with bipolar disorder, but executive functioning, working memory, and verbal and visual memory remained impaired in patients versus controls.[223]
Neuropsychological deficits in the areas of attention, working memory, and organization or problem-solving skills all contribute to academic difficulties.[224]
A mood-disordered parent and a child with bipolar disorder have particularly negative interactions and increased conflict. In one high-risk study, children who had problems with frontal lobe functioning appeared to have a greater risk of developing bipolar disorder, especially when a parent was very critical.[34]
This occurs at blood levels >1.5 mEq/L. Intentional overdose, drug interactions, a 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 intoxication.
The signs and symptoms of this complication may be neurologic (fine tremor, gait abnormality, hyperreflexia), gastrointestinal (nausea, vomiting, diarrhea), and cardiovascular (bradycardia, T-wave changes, conduction blocks). With increasing levels of lithium intoxication (2.5 to 3.5 mEq/L), slurring of speech, myoclonus, and a coarsening of the tremor may occur. Lithium blood levels above 3.5 mEq/L are life-threatening, as renal failure, stupor, seizures, and cardiovascular collapse are likely.[228]
PCOS is defined as chronic anovulation and hyperandrogenism, with or without actual polycystic ovaries. Clinical features include oligomenorrhea, hirsutism, and acne. PCOS is linked with insulin resistance and dyslipidemia, and many (but not all) patients with PCOS are obese. Although subject to considerable debate, a consensus appears to be emerging that administration of divalproex is associated with an increased risk of PCOS. Therefore, at each visit, patients taking valproic acid derivatives should be asked about menstrual dysfunction (irregular or missed menses), as well as about hirsutism and acne. Patients taking divalproex should be counseled regarding diet and exercise in an attempt to avoid weight gain.
If the patient is manifesting oligomenorrhea or hirsutism, then referral (pediatric, medical, endocrinologic, gynecologic) may be appropriate for institution of treatment with either a combination oral contraceptive or progestin. Additional treatment options include insulin-sensitizing agents (e.g., metformin), antiandrogens, topical treatments for acne, and various treatments for hirsutism. Other mood stabilizers (e.g., lithium, lamotrigine) do not appear to be associated with PCOS, and may be substituted for divalproex if needed.[225]
Completed suicide in adolescents is a rare event. However, one study found that 9% of deaths in bipolar disorder are due to suicide, and teens with mixed bipolar disorder have a nine times greater risk of suicide than teens without mental illness.[216][217]
Lithium is an effective treatment for reducing the risk of suicide in adults with mood disorders.[150]
Child maltreatment and neglect is strongly associated with suicidality in bipolar disorder.[69] More complex presentations, greater comorbidity, anxiety, duration of depression, and substance use also contribute to increased risk. Dialectical behavior therapy has been found to be protective.[16][218][219][220]
At recommended therapeutic doses for the management of bipolar disorder, second-generation antipsychotics are associated with a lower risk of neuromotor side effects when compared with first-generation antipsychotics, with little difference between these drugs.[148]
Although, as a class of medications, the second-generation antipsychotics carry a much lower risk for EPS than the first-generation antipsychotics, case reports exist for all of the second-generation antipsychotics linked to EPS and to tardive dyskinesia. Awareness of this potential neurologic adverse effect, early detection, and removal of the offending agent is the best preventive strategy.[157]
Early onset bipolar disorder is a significant predictor of first alcohol use.[230]
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