treatment of bipolar disorder treatment of bipolar disorder 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. bipolar disorder is often stigmatized as causing "crazy" behaviors, and physically alters the brain. this disorder affects the brain in many different ways such as, in the prefrontal cortex, which plays a big role in planning, attention, problem-solving, and memory, along with the hippocampus, which is essential for storing memories. it has been proven that patients with bipolar disorder have less total brain volume, grey and white matter, and more cerebral spinal fluid. 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. mood stabilisers treatmentnnt for depressive relapsennt for manic relapseefficacy in acute maniaefficacy in acute depressioncommon side effectsserious side effectssafety during pregnancyroutes of administration aripiprazole monotherapy506.2++-weight gain, nausea, vomiting, constipation, akathisia, dizziness, extrapyramidal symptoms, headache, insomnia, sedation, tremor, blurred vision, anxiety, restlessness, fatigueseizure (0.1-0.3%), suicidal behaviour, blood clots (<1%), agranulocytosis, leukopenia (<1%), neutropenia(<1%), pancreatitis (<0.1%), metabolic syndrome, neuroleptic malignant syndrome, tardive dyskinesia, angioedema (<1%), rhabdomyolysispregnancy category: b3 (au) c (us)oral, intramuscular aripiprazole adjunct to lithium/valproate33.3 10 ++-as aboveas aboveas aboveas above lamotrigine monotherapy20.250.4- ++/+ rash, abdominal pain, indigestion, diarrhoea, nausea, vomiting, asthenia, ataxia, coordination problem, dizziness, headache, insomnia, sedation, tremor, vertigo, blurred vision, diplopia, anxiety, depression, dysmenorrhoea, rhinitis, pain erythema multiforme (<0.1%), stevens–johnson syndrome (0.08-0.8%), toxic epidermal necrolysis (0.08-0.8%), anaemia (<0.1%), disseminated intravascular coagulation, eosinophilia(<0.1%), thrombocytopenia (<0.1%), liver failure, drug hypersensitivity syndrome, aseptic meningitis pregnancy category: d (au) c (us) appears to have a lower propensity than carbamazepine, lithium and valproate for causing birth defects but can still cause birth defects mucous membranes, oral lithium monotherapy6.14.4++ ++/+ acne, hypothyroidism, weight gain, gastritis, xerostomia, nausea, leukocytosis, fine tremor, hyperreflexia, deep tendon, nephrotoxicity, polyuria, potential sign of toxicity, increased thirst, potential sign of toxicitybradyarrhythmia (severe), brugada syndrome, sinus node dysfunction, transient reduction in peripheral circulation as a whole, erythema multiforme, ataxia, potential sign of toxicity, coma, pseudotumor cerebri, increased intracranial pressure and papilledema, seizure, blurred vision, potential sign of toxicity, tinnitus, potential sign of toxicity, giddiness, potential sign of toxicity, renal interstitial fibrosis, angioedemapregnancy category: d (au) d (us) risk of epstein's anomaly and other congenital heart defects. oral olanzapine monotherapy17.24.4+++ ++/+ orthostatic hypotension, peripheral edema (3% to 6%), hypercholesterolemia (up to 24%), hyperglycemia (0.1% to 17.4%), increased appetite (3% to 24%), increased prolactin level (31.2% to 61.1%), serum triglycerides raised (up to 40%), weight gain, constipation, xerostomia, akathisia, asthenia, dizziness, sedation, tremor, personality disorder (8%), accidental injury (4% to 12%) sudden cardiac death, diabetic coma with ketoacidosis, diabetic ketoacidosis, hyperglycemic hyperosmolar state, acute hemorrhagic pancreatitis, venous thromboembolism, immune hypersensitivity reaction, cerebrovascular disease, seizure (0.9% ), status epilepticus, suicidal intent (0.1% to 1% ), pulmonary embolism pregnancy category: c (au) c (us) oral, intramuscular olanzapine adjunct to lithium/valproate6.211.2+++ - as above as above as above as above quetiapine monotherapy3.32.4++ +++ orthostatic hypertension, tachycardia (0.5% to 7%), serum cholesterol raised (7% to 18%), serum triglycerides raised (8% to 22%), weight gain (3% to 23%), abdominal pain, constipation, increased appetite, indigestion, vomiting, xerostomia, increased liver enzymes, backache, asthenia, dizziness, extrapyramidal signs, headache, insomnia, lethargy, sedation, tremor, agitation (6% to 20%), nasal congestion, pharyngitis (4% to 6%), fatigue, pain syncope (0.3% to 1%), diabetic ketoacidosis, pancreatitis, agranulocytosis, leukopenia, neutropenia (0.3%), anaphylaxis, seizure (0.05% to 0.5%), tardive dyskinesia (0.1% to less than 5%), suicidal thoughts, priapism, neuroleptic malignant syndrome (rare ) pregnancy category: b3 (au) c (us) oral quetiapine plus lithium/valproate5.97.1+++/++ +++ as above as above as above as above risperidone436.4+++ - rash, hyperprolactinaemia, weight gain, constipation, diarrhoea, excessive salivation, increased appetite, indigestion, nausea, vomiting, upper abdominal pain, dry mouth, extrapyramidal side effects, dizziness, sedation, akathisia, blurred vision, anxiety, cough, nasal congestion, nasopharyngitis, pain in throat, upper respiratory tract infection, fatigue and generalised pains prolonged qt interval, sudden cardiac death, syncope, diabetic ketoacidosis, hypothermia, pancreatitis, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura, stroke, seizure, tardive dyskinesia, priapism, pulmonary embolism, neuroleptic malignant syndrome pregnancy category: b3 (au) c (us) oral, intramuscular risperidone plus treatment as usual15.87.9+++ - as above as above as above as above valproate monotherapy10.521.3++/+ - abdominal pain, diarrhoea, indigestion, loss of appetite, nausea, vomiting, asthenia, dizziness, feeling nervous, headache, insomnia, sedation, tremor, amblyopia, blurred vision, diplopia, infectious disease, influenza palpitation, tachycardia, hyperammonaemia, pancreatitis, thrombocytopaenia, liver failure, immune hypersensitivity reaction, hyperammonaemic encephalopathy, deafness pregnancy category: d (au) d (us) has the highest propensity of all anticonvulsants for causing birth defects. around 6-11% of children born to mothers that used the drug during pregnancy are born with birth defects. oral ziprasidone and treatment as usual55.114.1++/+ - rash, weight gain, constipation, diarrhoea, indigestion, nausea, vomiting, xerostomia, akathisia, anxiety, asthenia, extrapyramidal side effects, dizziness, headache, sedation, abnormal vision, respiratory tract infection prolonged qt interval, syncope, torsades de pointes, diabetes mellitus, hyperglycaemia, hyperprolactinaemia, dysphagia, bone marrow depression, neuroleptic malignant syndrome, seizure, tardive dyskinesia, priapism pregnancy category: b3 (au) c (us) oral, intramuscular legend: - negligible/very low/clinically insignificant effect + weak effect ++ moderate-level effect +++ strong effect regulatory status of mood stabilisers drugfda approved for acute mania/mixed episodes?fda approved for bipolar depression?fda approved for bipolar maintenance?tga approved for acute mania/mixed episodes?tga approved for bipolar depression?tga approved for bipolar maintenance?mhra approved for acute mania/mixed episodes?mhra approved for bipolar depressionmhra approved for bipolar maintenance aripiprazoleyesnoyes (as an adjunct, yes)nonoyesyesnoyes (for mania prevention) asenapineyesnonoyesnoyesyesnono carbamazepineyesnonononoyesnonoyes cariprazineyesyesno haloperidolnononoyesnonononono lamotriginenonoyesnonoyesnonoyes (depressive episodes) lithiumyesnoyesyesnoyesyesnoyes olanzapineyesno (yes when in conjunction with fluoxetine)yesyesnoyes (as an adjunct to valproate/lithium)yesnono quetiapineyesyesyesyesyesyesyesyesyes lurasidoneyes risperidoneyesnoyesyesnoyesyesnono valproateyesnonononoyesyesnoyes ziprasidoneyesnono (yes as adjunct)yesnonononono zuclopenthixolnononoyesnonononono mood stabilizers lithium salts main article: lithium pharmacology 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