Detailed analysis of management techniques for bipolar disorders
The emphasis of the treatment of bipolar disorder is on effective management of the long-term course of the illness, which can involve treatment of emergent symptoms. Treatment methods include pharmacological and psychological techniques.
Bipolar disorder is a serious and debilitating mental health disorder, which causes patients to experience extreme highs and lows, such as mania and major depression.
Principles.
The primary treatment for bipolar disorder consists of medications called mood stabilizers, which are used to prevent or control episodes of mania or depression. Medications from several classes have mood stabilizing activity. Many individuals may require a combination of medication to achieve full remission of symptoms. As it is impossible to predict which medication will work best for a particular individual, it may take some trial and error to find the best medication or combination for a specific patient. Psychotherapy also has a role in the treatment of bipolar disorder. The goal of treatment is not to cure the disorder but rather to control the symptoms and the course of the disorder. Generally speaking, maintenance treatment of bipolar disorder continues long after symptom control has been achieved.
Following diagnostic evaluation, the treating clinician must determine the optimal treatment setting in order to ensure the patient's safety. Assessment of suicide risk is key, as the rate of suicide completion among those with bipolar disorder may be as high as 10–15%. Hospitalization should be considered in patients whose judgment is significantly impaired by their illness, and those who have not responded to outpatient treatment; this may need to be done on an involuntary basis. Treatment setting should regularly be re-evaluated to ensure that it is optimal for the patient's needs.
Legend:
- negligible/very low/clinically insignificant effect
+ weak effect
 moderate-level effe.
+ strong effe.
Mood stabilizers.
Lithium salts.
Lithium salts have been used for centuries as a first-line treatment for bipolar disorder. In ancient times, doctors would send their mentally ill patients to drink from "alkali springs" as a treatment. Although they were not aware of it, they were actually prescribing lithium, which was present in high concentration within the waters. The therapeutic effect of lithium salts appears to be entirely due to the lithium ion, Li+.
Its exact mechanism of action is uncertain, although there are several possibilities such as inhibition of inositol monophosphatase, modulation of G proteins or regulation of gene expression for growth factors and neuronal plasticity. There is strong evidence for its effectiveness in acute treatment and prevention of recurrence of mania. It can also be effective in bipolar depression, although the evidence is not as strong. It is also effective in reducing the risk of suicide in patients with mood disorders.
Potential side effects from lithium include gastrointestinal upset, tremor, sedation, excessive thirst, frequent urination, cognitive problems, impaired motor coordination, hair loss, and acne. Excessive levels of lithium can be harmful to the kidneys, and increase the risk of side effects in general. As a result, kidney function and blood levels of lithium are monitored in patients being treated with lithium. Therapeutic plasma levels of lithium range from 0.5 to 1.5 mEq/L, with levels of 0.8 or higher being desirable in acute mania.
Lithium levels should be above 0.6 mEq/L to reduce both manic and depressive episodes in patients. A recent review concludes that the standard lithium serum level should be 0.60–0.80 mmol/L with optional reduction to 0.40 0.60 mmol/L in case of good response but poor tolerance or an increase to 0.80 1.00 mmol/L in case of insufficient response and good tolerance.
Monitoring is generally more frequent when lithium is being initiated, and the frequency can be decreased once a patient is stabilized on a given dose. Thyroid hormones should also be monitored periodically, as lithium can increase the risk of hypothyroidism.
Anticonvulsants.
A number of anti-convulsant drugs are used as mood stabilizers, and the suspected mechanism is related to the theory that mania can "kindle" further mania, similar to the kindling model of seizures. Valproic acid, or valproate, was one of the first anti-convulsants tested for use in bipolar disorder. It has proven to be effective for treating acute mania. The mania prevention and antidepressant effects of valproic acid have not been well demonstrated. Valproic acid is less effective than lithium at preventing and treating depressive episodes.
Carbamazepine was the first anti-convulsant shown to be effective for treating bipolar mania. It has not been extensively studied in bipolar depression. It is generally considered a second-line agent due to its side effect profile. Lamotrigine is considered a first-line agent for the treatment of bipolar depression. It is effective in preventing the recurrence of both mania and depression, but it has not proved useful in treating acute mania.
Zonisamide (trade name Zonegran), another anti-convulsant, also may show promise in treating bipolar depression. Various other anti-convulsants have been tested in bipolar disorder, but there is little evidence of their effectiveness. Other anti-convulsants effective in some cases and being studied closer include phenytoin, levetiracetam, pregabalin and valnoctamide.
Each anti-convulsant agent has a unique side-effect profile. Valproic acid can frequently cause sedation or gastrointestinal upset, which can be minimized by giving the related drug divalproex, which is available in an enteric-coated tablet. These side effects tend to disappear over time. According to studies conducted in Finland in patients with epilepsy, valproate may increase testosterone levels in teenage girls and produce polycystic ovary syndrome in women who began taking the medication before age 20. Increased testosterone can lead to polycystic ovary syndrome with irregular or absent menses, obesity, and abnormal growth of hair. Therefore, young female patients taking valproate should be monitored carefully by a physician. Excessive levels of valproate can lead to impaired liver function, and liver enzymes and serum valproate level, with a target of 50–125 μg/L, should be monitored periodically.
Side effects of carbamazepine include blurred vision, double vision, ataxia, weight gain, nausea, and fatigue, as well as some rare but serious side effects such as blood dyscrasias, pancreatitis, exfoliative dermatitis, and hepatic failure. Monitoring of liver enzymes, platelets, and blood cell counts are recommended.
Lamotrigine generally has minimal side effects, but the dose must be increased slowly to avoid rashes, including Stevens-Johnson syndrome (SJS) and exfoliative dermatitis.
Atypical antipsychotic drugs.
Antipsychotics work best in the manic phase of bipolar disorder.
Second-generation or atypical antipsychotics (including aripiprazole, olanzapine, quetiapine, paliperidone, risperidone, and ziprasidone) have emerged as effective mood stabilizers. The evidence for this is fairly recent, as in 2003 the American Psychiatric Press noted that atypical anti-psychotics should be used as adjuncts to other anti-manic drugs because their mood stabilizing properties had not been well established. The mechanism is not well known, but may be related to effects on glutamate activity. Several studies have shown atypical antipsychotics to be effective both as single-agent and adjunctive treatments. Antidepressant effectiveness varies, which may be related to different serotonergic and dopaminergic receptor binding profiles. Quetiapine and the combination of olanzapine and fluoxetine have both demonstrated effectiveness in bipolar depression.
In light of recent evidence, olanzapine (Zyprexa) has been FDA approved as an effective monotherapy for the maintenance of bipolar disorder. A head-to-head randomized control trial in 2005 has also shown olanzapine monotherapy to be just as effective and safe as lithium in prophylaxis.
The atypical antipsychotics differ somewhat in side effect profiles, but most have some risk of sedation, weight gain, and extrapyramidal symptoms (including tremor, stiffness, and restlessness). They may also increase the risk of metabolic syndrome, so metabolic monitoring should be performed regularly, including checks of serum cholesterol, triglycerides, and glucose, weight, blood pressure, and waist circumference. Taking antipsychotics for long periods or at high doses can also cause tardive dyskinesia — a sometimes incurable neurological disorder resulting in involuntary, repetitive body movements. The risk of tardive dyskinesia appears to be lower in second-generation antipsychotics than in first-generation antipsychotics but as with first-generation drugs, increases with time spent on medications and in older patients.
New treatments.
A variety of other agents have been tried in bipolar disorder, including benzodiazepines, calcium channel blockers, L-methylfolate, and thyroid hormone. Modafinil (Provigil) and pramipexole (Mirapex) have been suggested for treating cognitive dysfunction associated with bipolar depression, but evidence supporting their use is quite limited. In addition, riluzole, a glutamatergic drug used in ALS has been studied as an adjunct or monotherapy treatment in bipolar depression, with mixed and inconsistent results. The selective estrogen receptor modulator medication tamoxifen has shown rapid and robust efficacy treating acute mania in bipolar patients. This action is likely due not to tamoxifen's estrogen-modulating properties, but due to its secondary action as an inhibitor of protein Kinase C.
Cognitive effects of mood stabilizers.
Bipolar patients taking antipsychotics have lower scores on tests of memory and full-scale IQ than patients taking other mood stabilisers. Use of both typical and atypical antipsychotics is associated with risk of cognitive impairment, but the risk is higher for antipsychotics with more sedating effects.
Among bipolar patients taking anticonvulsants, those on lamotrigine have a better cognitive profile than those on carbamazepine, valproate, topiramate, and zonisamide.
Although decreased verbal memory and slowed psychomotor speed are common side effects of lithium use
these side effects usually disappear after discontinuation of lithium. Lithium may be protective of cognitive function in the long term since it promotes neurogenesis in the hippocampus and increases grey matter volume in the prefrontal cortex.
Antidepressants.
Antidepressants are used with caution in bipolar disorder, as they may not be effective and may even induce mania. They are generally not used alone, but may be considered as an adjunct to lithium.
A recent large-scale study found that severe depression in patients with bipolar disorder responds no better to a combination of antidepressant medications and mood stabilizers than it does to mood stabilizers alone and that antidepressant use does not hasten the emergence of manic symptoms in patients with bipolar disorder.
The concurrent use of an antidepressant and a mood stabilizer, instead of mood stabilizer monotherapy, may lower the risk of further bipolar depressive episodes in patients whose most recent depressive episode has been resolved. However, some studies have also found that antidepressants pose a risk of inducing hypomania or mania, sometimes in individuals with no prior history of mania. Saint John's Wort, a naturally occurring compound, is thought to function in a fashion similar to man-made antidepressants, and there are reports that suggest that it can also induce mania. For these reasons, some psychiatrists are hesitant to prescribe antidepressants for the treatment of bipolar disorder unless mood stabilizers have failed to have an effect, however, others feel that antidepressants still have an important role to play in treatment of bipolar disorder.
Side effects vary greatly among different classes of antidepressants.
Antidepressants are helpful in preventing suicides in people with bipolar disorder when they go in for the depressive phase.
NMDA-receptor antagonists.
In a double-blind, placebo-controlled, proof-of-concept study, researchers administered an N-methyl-d-aspartate–receptor antagonist (ketamine) to 18 patients already on treatment with lithium (10 patients) or valproate (8 patients) for bipolar depression. From 40 minutes following intravenous injection of ketamine hydrochloride (0.5 mg/kg), the researchers observed significant improvements in depressive symptoms, as measured by standard tools, that were maintained for up to 3 days, an effect not observed in subjects who received the placebo. Five subjects dropped out of the ketamine study; of these, four were taking valproate and one was being treated with lithium. One patient showed signs of hypomania following ketamine administration and two experienced low mood. This study demonstrates a rapid-onset antidepressant effect of ketamine in a small group of patients with bipolar depression. The authors acknowledged the study's limitations, including the dissociative disturbances in patients receiving ketamine that could have compromised the study blinding, and they emphasised the need for further research.
A more recent double-blind, placebo-controlled study by the same group found that ketamine treatment resulted in a similarly rapid alleviation of suicidal ideation in 15 patients with bipolar depression.
Ketamine is used as a dissociative anaesthetic, and is a Class C substance in the United Kingdom; as such, it is only be used psychiatrically under the direction of a health professional.
Dopamine agonists.
In a single controlled study of twenty one patients, the dopamine D3 receptor agonist pramipexole was found to be highly effective in the treatment of bipolar depression. Treatment was initiated at 0.125 mg thrice daily and increased at a rate of 0.125 mg thrice daily to a limit of 4.5 mg per day until the patients' condition satisfactorily responded to the medication or they could not abide the side effects. The final average dosage was 1.7 mg ± 0.90 mg per day. The incidence of hypomania in the treatment group was no