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.
- 1 Principles
- 2 Mood stabilizers
- 3 Antidepressants
- 4 NMDA-receptor antagonists
- 5 Dopamine agonists
- 6 Psychotherapy and Cognitive Behavioral Therapy
- 7 Jungian therapy
- 8 Lifestyle changes
- 9 Other treatments
- 10 See also
- 11 References
- 12 External links
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.
|Treatment||NNT for depressive relapse||NNT for manic relapse||Efficacy in Acute Mania||Efficacy in Acute Depression||Common Side Effects||Serious Side Effects||Safety during pregnancy||Routes of Administration|
|Aripiprazole monotherapy||50||6.2||++||-||Weight gain, nausea, vomiting, constipation, akathisia, dizziness, extrapyramidal symptoms, headache, insomnia, sedation, tremor, blurred vision, anxiety, restlessness, fatigue||Seizure (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%), rhabdomyolysis||Pregnancy Category:
|Aripiprazole adjunct to lithium/valproate||33.3||10||++||-||As above||As above||As above||As above|
|Lamotrigine monotherapy||20.2||50.4||-||++/+||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:||Mucous membranes, oral|
|Lithium monotherapy||6.1||4.4||++||++/+||Acne, hypothyroidism, weight gain, gastritis, xerostomia, nausea, leukocytosis, fine tremor, Hyperreflexia, Deep tendon, Nephrotoxicity, Polyuria, Potential sign of toxicity, Increased thirst, Potential sign of toxicity||Bradyarrhythmia (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, Angioedema||Pregnancy Category:||Oral|
|Olanzapine monotherapy||17.2||4.4||+++||++/+||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:||Oral, intramuscular|
|Olanzapine adjunct to lithium/valproate||6.2||11.2||+++||-||As above||As above||As above||As above|
|Quetiapine monotherapy||3.3||2.4||++||+++||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:||Oral|
|Quetiapine plus lithium/valproate||5.9||7.1||+++/++||+++||As above||As above||As above||As above|
|Risperidone||4||36.4||+++||-||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:||Oral, Intramuscular|
|Risperidone plus treatment as usual||15.8||7.9||+++||-||As above||As above||As above||As Above|
|Valproate monotherapy||10.5||21.3||++/+||-||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:
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.
|Ziprasidone and treatment as usual||55.1||14.1||++/+||-||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:||Oral, intramuscular|
- negligible/very low/clinically insignificant effect
+ weak effect
++ moderate-level effect
+++ strong effect
Regulatory status of mood stabilisers
|Drug||FDA 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 depression||MHRA approved for bipolar maintenance|
|Aripiprazole||Yes||No||Yes (as an adjunct, yes)||No||No||Yes||Yes||No||Yes (for mania prevention)|
|Lamotrigine||No||No||Yes||No||No||Yes||No||No||Yes (depressive episodes)|
|Olanzapine||Yes||No (yes when in conjunction with fluoxetine)||Yes||Yes||No||Yes (as an adjunct to valproate/lithium)||Yes||No||No|
|Ziprasidone||Yes||No||No (yes as adjunct)||Yes||No||No||No||No||No|
The use of lithium salts, such as lithium carbonate, as a treatment of bipolar disorder was first discovered by John Cade, an Australian psychiatrist who published a paper on the use of lithium in 1949.
Lithium salts had been used for a while, 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. They did not know it, but they were really prescribing lithium, which was present in high concentration in 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 of 0.5–1.5 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.
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.
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.
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 dyskenia 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
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) show promise in treating cognitive deterioration related to bipolar depression. In addition Riluzole, an ALS treatment, has been shown to be effective treatment. The breast cancer medicine tamoxifen has shown quick response to manic phases.
Antidepressants should only be used with caution in bipolar disorder, as they may not be effective and may even induce mania. They should not be 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, although a naturally occurring compound, is thought to function in a fashion similar to man-made antidepressants, and so unsurprisingly, 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 suffering from bipolar disorder when they go in for the depressive phase.
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.
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 t.i.d. and increased at a rate of 0.125 mg t.i.d. to a limit of 4.5 mg qd 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 ± .90 mg qd. The incidence of hypomania in the treatment group was no greater than in the control group.
Psychotherapy and Cognitive Behavioral Therapy
Certain types of psychotherapy, used in combination with medication, may provide some benefit in the treatment of bipolar disorders. Psychoeducation has been shown to be effective in improving patients' compliance with their lithium treatment. Evidence of the efficacy of family therapy is not adequate to support unrestricted recommendation of its use. There is "fair support" for the utility of cognitive therapy. Evidence for the efficacy of other psychotherapies is absent or weak, often not being performed under randomized and controlled conditions. Well-designed studies have found interpersonal and social rhythm therapy to be ineffective.
Although medication and psychotherapy cannot cure the illness, therapy can often be valuable in helping to address the effects of disruptive manic or depressive episodes that have hurt a patient's career, relationships or self-esteem. Therapy is available not only from psychiatrists but from social workers, psychologists and other licensed counselors.
Jungian authors have likened the mania and depression of bipolar disorder to the Jungian archetypes 'puer' and 'senex'. The puer archetype is defined by the behaviors of spontaneity, impulsiveness, enthusiasm or mania and is symbolized by characters such as Peter Pan or the Greek god Hermes. The senex archetype is defined by behaviors of order, systematic thought, caution, and depression and is symbolized by characters such as the Roman god Saturn or the Greek god Kronos. Jungians conceptualize the puer and senex as a coexistent bipolarity appearing in human behavior and imagination, but in neurotic manifestations appears as extreme oscillations and as unipolar manifestations. In the case of the split puer-senex bipolarity the therapeutic task is to bring the puer and senex back into correlation by working with the patient's mental imagery."
If sleeping is disturbed, the symptoms can occur. Sleep disruption may actually exacerbate the mental illness state. Those who do not get enough sleep at night, sleep late and wake up late, or go to sleep with some disturbance(e.g. music or charging devices) have a greater chance of having the symptoms and, in addition, depression. It is highly advised to not sleep too late and to get enough sleep of high quality.
Self-management & self-awareness
Understanding the symptoms, when they occur and ways to control them using appropriate medications and psychotherapy has given many people diagnosed with bipolar disorder a chance at a better life. Prodrome symptom detection has been shown to be used effectively to anticipate onset of manic episodes and requires high degree of understanding of one's illness. Because the offset of the symptoms is often gradual, recognizing even subtle mood changes and activity levels is important in avoiding a relapse. Maintaining a mood chart is a specific method used by patients and doctors to identify mood, environmental and activity triggers.
Forms of stress may include having too much to do, too much complexity and conflicting demands among others. There are also stresses that come from the absence of elements such as human contact, a sense of achievement, constructive creative outlets, and occasions or circumstances that will naturally elicit positive emotions. Stress reduction will involve reducing things that cause anxiety and increasing those that generate happiness. It is not enough to just reduce the anxiety.
Co-morbid substance use disorder
Co-occurring substance misuse disorders, which are extremely common in bipolar patients can cause a significant worsening of bipolar symptomatology and can cause the emergence of affective symptoms. The treatment options and recommendations for substance use disorders is wide but may include certain pharmacological and nonpharmacological treatment options.
Omega-3 fatty acids
Omega-3 fatty acids may also be used as a treatment for bipolar disorder, particularly as a supplement to medication. An initial clinical trial by Stoll et al. produced positive results. However, since 1999 attempts to confirm this finding of beneficial effects of omega-3 fatty acids in several larger double-blind clinical trials have produced inconclusive results. It was hypothesized that the therapeutic ingredient in omega-3 fatty acid preparations is eicosapentaenoic acid (EPA) and that supplements should be high in this compound to be beneficial. A 2008 Cochrane systematic review found limited evidence to support the use of Omega-3 fatty acids to improve depression but not mania as an adjunct treatment for bipolar disorder.
Omega-3 fatty acids may be found in fish, fish oils, algae, and to a lesser degree in other foods such as flaxseed, flaxseed oil and walnuts. Although the benefits of Omega-3 fatty acids remain debated, they are readily available at drugstores and supermarkets, relatively inexpensive, and have few known side effects. (All of these oils, however, have the capacity to exacerbate GERD—food sources may be a good alternative in such cases.)[medical citation needed]
Exercise has also been shown to have antidepressant effects.
Electroconvulsive therapy (ECT) may have some effectiveness in mixed mania states, and good effectiveness in bipolar depression, particularly in the presence of psychosis. It may also be useful in the treatment of mania that is non-responsive to medications.
The most frequent side effects of ECT include memory impairment, headaches, and muscle aches. In some instances, ECT can produce significant and long-lasting cognitive impairment, including anterograde amnesia, and retrograde amnesia.
Because many of the medications that are effective in treating epilepsy are also effective as mood stabilizers, it has been suggested that the ketogenic diet— used for treating pediatric epilepsy— could have mood stabilizing effects. Ketogenic diets are diets that are high in fat and low in carbohydrates, and force the body to use fat for energy instead of sugars from carbohydrates. This causes a metabolic response similar to that seen in the body during fasting. This idea has not been tested by clinical research, and until recently, was entirely hypothetical. Recently, however, two case studies have been described where ketogenic diets were used to treat bipolar II. In each case, the patients found that the ketogenic diet was more effective for treating their disorder than medication and were able to discontinue the use of medication. The key to efficacy appears to be ketosis, which can be achieved either with a classic high-fat ketogenic diet, or with a low-carbohydrate diet similar to the induction phase of the Atkins Diet. The mechanism of action is not well understood. It is unclear whether the benefits of the diet produce a lasting improvement in symptoms (as is sometimes the case in treatment for epilepsy) or whether the diet would need to be continued indefinitely to maintain symptom remission.
More research is needed. Stanford University Medical School attempted a study using a ketogenic diet protocol on bipolar patients. However due to the lack of ability to attract subjects the trial was never started.
The role of Cannabinoids
Acute cannabis intoxication transiently produces perceptual distortions, psychotic symptoms and reduction in cognitive abilities in healthy persons and in severe mental disorder, and may impair the ability to safely operate a motor vehicle.
Cannabis use is common in BD; and is a risk factor for a more severe course of BD by increasing frequency and duration of episodes. It is also reported to reduce age at onset.
- Stahl, S. M. (2008). Stahl's Essential Psychopharmacology: Neuroscientific basis and practical applications. Cambridge University Press.
- American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Bipolar Disorder, Second Edition", 2002
- Popovic, D; Reinares, M; Goikolea, JM; Bonnin, CM; Gonzalez-Pinto, A; Vieta, E (May 2012). "Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder". European Neuropsychopharmacology 22 (5): 339–346. doi:10.1016/j.euroneuro.2011.09.008. PMID 22000157.
- Truven HealthAnalytics, Inc. DRUGDEX® System (Internet) [cited 2013 Sep 9]. GreenwoodVillage, CO: Thomsen Healthcare; 2013.
- Galbally, M; Roberts, M; Buist, A (November 2010). "Mood Stabilizers in Pregnancy: A Systematic Review". The Australian and New Zealand Journal of Psychiatry 44 (11): 967–977. doi:10.3109/00048674.2010.506637 (inactive 2015-10-28). PMID 21034180.
- Cipriani, A; Barbui, C; Salanti, G; Rendell, J; Brown, R; Brown, R; Stockton, S; Purgato, M; Spineli, LM; Goodwin, GM; Geddes, JR (October 2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis". The Lancet 378 (9799): 1306–1315. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976.
- Ryan, RSM; Jordan, B; Martin, J; Wagle, SMS; Amin, S; Clarke, SE; et al. (2013). British National Formulary 65. London: Pharmaceutical Press. ISBN 978-0-85711-084-8.
- "Australian Medicines Handbook". Australian Medicines Handbook Pty Ltd. 2013.
- Hendrick, V; Keck, P; Wilkins-Haug, L (14 June 2013). "Bipolar disorder in pregnant women: Treatment of mania, hypomania, and mixed episodes". UpToDate®. Wolters Kluwer. Retrieved 10 October 2013.
- Ryan RSM, Jordan B, Martin J, Wagle SMS, Amin S, Clarke SE, et al. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
- Therapeutic Goods Administration. TGA eBusiness Services [Internet]. Australian Government Department of Health and Ageing.; [cited 2013 Sep 15]. Available from: https://www.ebs.tga.gov.au/
- Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Sep 15]. Greenwood Village, CO: Thomsen Healthcare; 2013.
- Baldessarini, R. J.; Tondo, L.; Hennen, J. (2003). "Lithium treatment and suicide risk in major affective disorders: Update and new findings". The Journal of clinical psychiatry. 64 Suppl 5: 44–52. PMID 12720484.
- Hales E. and Yudofsky, J. A., eds, The American Psychiatric Press Textbook of Psychiatry, Washington, DC: American Psychiatric Publishing, Inc., 2003
- Nolen, WA; Weisler, RH (Feb 2013). "The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144).". Bipolar disorders 15 (1): 100–9. doi:10.1111/bdi.12027. PMID 23228201.
- Kessing, L. V.; Hellmund, G.; Geddes, J. R.; Goodwin, G. M.; Andersen, P. K. (2011). "Valproate v. Lithium in the treatment of bipolar disorder in clinical practice: Observational nationwide register-based cohort study". The British Journal of Psychiatry 199 (1): 57–63. doi:10.1192/bjp.bp.110.084822. PMID 21593515.
- Frederick K. Goodwin M.D. "The Accurate Diagnosis and Long-Term Treatment of Bipolar Depression"
- Clinical trial number NCT00140179 for "Valnoctamide in Mania" at ClinicalTrials.gov
- Geddes, JR; Miklowitz, DJ (May 11, 2013). "Treatment of bipolar disorder.". Lancet 381 (9878): 1672–82. doi:10.1016/s0140-6736(13)60857-0. PMID 23663953.
- American Psychiatric Association, "Guideline Watch: Practice Guide for the Treatment of Patients with Bipolar Disorder, 2nd ed", 2005
- Now Approved: ZYPREXA for maintenance therapy for bipolar disorder. Official Zyprexa Website.
- Tohen, M.; Greil, W.; Calabrese, J. R.; Sachs, G. S.; Yatham, L. N.; Oerlinghausen, B. M.; Koukopoulos, A.; Cassano, G. B.; et al. (2005). "Olanzapine Versus Lithium in the Maintenance Treatment of Bipolar Disorder: A 12-Month, Randomized, Double-Blind, Controlled Clinical Trial". American Journal of Psychiatry 162 (7): 1281–90. doi:10.1176/appi.ajp.162.7.1281. PMID 15994710.
- Correll, C. U.; Leucht, S; Kane, J. M. (2004). "Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies". American Journal of Psychiatry 161 (3): 414–425. PMID 14992963.
- Zarate, Carlos A.; Singh, Jaskaran B.; Carlson, Paul J.; Quiroz, Jorge; Jolkovsky, Libby; Luckenbaugh, David A.; Manji, Husseini K. (2007). "Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: A pilot study". Bipolar Disorders 9 (6): 561–70. doi:10.1111/j.1399-5618.2007.00530.x. PMID 17845270.
- Sachs, Gary S.; Nierenberg, Andrew A.; Calabrese, Joseph R.; Marangell, Lauren B.; Wisniewski, Stephen R.; Gyulai, Laszlo; Friedman, Edward S.; Bowden, Charles L.; et al. (2007). "Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression". New England Journal of Medicine 356 (17): 1711–22. doi:10.1056/NEJMoa064135. PMID 17392295.
- Altshuler, L.; Suppes, T.; Black, D.; Nolen, W. A.; Keck Jr, P. E.; Frye, M. A.; McElroy, S.; Kupka, R.; et al. (2003). "Impact of Antidepressant Discontinuation After Acute Bipolar Depression Remission on Rates of Depressive Relapse at 1-Year Follow-Up". American Journal of Psychiatry 160 (7): 1252–62. doi:10.1176/appi.ajp.160.7.1252. PMID 12832239.
- Truman, C. J.; Goldberg, J. F.; Ghaemi, S. N.; Baldassano, C. F.; Wisniewski, S. R.; Dennehy, E. B.; Thase, M. E.; Sachs, G. S. (2007). "Self-reported history of manic/hypomanic switch associated with antidepressant use: Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)". The Journal of clinical psychiatry 68 (10): 1472–9. doi:10.4088/jcp.v68n1002. PMID 17960960.
- Nierenberg, A. A.; Burt, T.; Matthews, J.; Weiss, A. P. (1999). "Mania associated with St. John's wort". Biological Psychiatry 46 (12): 1707–8. doi:10.1016/S0006-3223(99)00233-4. PMID 10624554.
- Leon, A. C.; Fiedorowicz, J. G.; Solomon, D. A.; Li, C; Coryell, W. H.; Endicott, J; Fawcett, J; Keller, M. B. (2014). "Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders". The Journal of Clinical Psychiatry 75 (7): 720–7. doi:10.4088/JCP.13m08744. PMC 4142755. PMID 25093469.
- Diazgranados, N.; Ibrahim, L.; Brutsche, N. E.; Newberg, A.; Kronstein, P.; Khalife, S.; Kammerer, W. A.; Quezado, Z.; et al. (2010). "A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression". Archives of General Psychiatry 67 (8): 793–802. doi:10.1001/archgenpsychiatry.2010.90. PMC 3000408. PMID 20679587.
- Zarate, C. A. Jr; Brutsche, N. E.; Ibrahim, L.; Franco-Chaves, J.; Diazgranados, N.; Cravchik, A.; Selter, J.; Marquardt, C. A.; Liberty, V.; Luckenbaugh, D. A. (Jun 1, 2012). "Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.". Biological Psychiatry 71 (11): 939–46. doi:10.1016/j.biopsych.2011.12.010. PMC 3343177. PMID 22297150.
- Zarate, C. A.; Payne, J. L.; Singh, J. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biol. Psychiatry 56 (1): 54–60. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473.
- Cochran, Susan D. (1984). "Preventing medical noncompliance in the outpatient treatment of bipolar affective disorders". Journal of Consulting and Clinical Psychology 52 (5): 873–8. doi:10.1037/0022-006X.52.5.873. PMID 6501672.
- Justo, LP; Soares, BG; Calil, HM; Depression, Anxiety and Neurosis Group (2007). "Family interventions for bipolar disorder". Cochrane Database of Systematic Reviews (4): CD005167. doi:10.1002/14651858.CD005167.pub2. PMID 17943843.
- Parikh, S. V.; Kusumakar, V.; Haslam, D. R.; Matte, R.; Sharma, V.; Yatham, L. N. (1997). "Psychosocial interventions as an adjunct to pharmacotherapy in bipolar disorder". Canadian journal of psychiatry. Revue canadienne de psychiatrie. 42 Suppl 2: 74S–78S. PMID 9288439.
- Goodnick, Paul J. (2002). "Psychosocial Treatments for Bipolar Disorder: Is There Evidence That They Work?". In Sartorius, Norman; Maj, Mario; Akiskal, Hagop S.; Juan José López-Ibor. Bipolar disorder. WPA Series in Evidence & Experience in Psychiatry 5. Chichester: John Wiley & Sons. p. 338. ISBN 0-471-56037-5.
- Frank, Ellen; Swartz, Holly A.; Mallinger, Alan G.; Thase, Michael E.; Weaver, Elizabeth V.; Kupfer, David J. (1999). "Adjunctive psychotherapy for bipolar disorder: Effects of changing treatment modality". Journal of Abnormal Psychology 108 (4): 579–87. doi:10.1037/0021-843X.108.4.579. PMID 10609422.
- Hillman, J. Ed. Puer Papers, Spring Publications (1979)
- Hillman, J. (2005) Senex and Puer Spring Publications. p. 30–66
- Zoja, Luigi (1987). "Analytical Psychology and the Metapsychology of Feelings:". Journal of Analytical Psychology 32 (1): 47–55. doi:10.1111/j.1465-5922.1987.00047.x. PMID 3804855.
- Vitale, A., (1973) "Saturn: The Transformation of the Father" in Fathers and Mothers: Five Papers on the Archetypal Background of Family Psychology, edited by Patricia Berry, pp. 5–39. Spring Publications
- Thompson, J. (2012) A Jungian Approach to Bipolar Disorder, Soul Books. p. 1–10
- Zoja, L. (1995) Growth and Guilt Routledge Press, p. 131–132
- Thompson, J. (2012) A Jungian Approach to Bipolar Disorder, Soul Books
- Morriss, RK; Faizal, MA; Jones, AP; Williamson, PR; et al. (2007). "Interventions for helping people recognise early signs of recurrence in bipolar disorder". Depression, Anxiety and Neurosis Group. Cochrane Database of Systematic Reviews (1): CD004854. doi:10.1002/14651858.CD004854.pub2. PMID 17253526.
- Sahoo, MK; Chakrabarti, S; Kulhara, P (February 2012). "Detection of prodromal symptoms of relapse in mania & unipolar depression by relatives & patients". Indian Journal of Medical Research 135 (2): 177–83. PMC 3336848. PMID 22446859.
- "Daily Mood Chart" (PDF). Good Health Guidelines for People With Bipolar Disorder. CignaBehavioral. February 2008. Retrieved 2014-06-23.
- Miklowitz, David (2002). The Bipolar Disorder Survival Guide. New York: The Guilford Press. p. 154. ISBN 1-57230-712-9.
- Cerullo, Michael A.; Strakowski, Stephen M. (2007). "The prevalence and significance of substance use disorders in bipolar type I and II disorder". Substance Abuse Treatment, Prevention, and Policy 2: 29. doi:10.1186/1747-597X-2-29.
- Stoll, A. L.; Severus, W. E.; Freeman, M. P.; Rueter, S.; Zboyan, H. A.; Diamond, E.; Cress, K. K.; Marangell, L. B. (1999). "Omega 3 Fatty Acids in Bipolar Disorder: A Preliminary Double-blind, Placebo-Controlled Trial". Archives of General Psychiatry 56 (5): 407–12. doi:10.1001/archpsyc.56.5.407. PMID 10232294.
- Osher, Yamima; Bersudsky, Yuly; Belmaker, R. H. (2005). "Omega-3 Eicosapentaenoic Acid in Bipolar Depression". The Journal of Clinical Psychiatry 66 (6): 726–9. doi:10.4088/JCP.v66n0608. PMID 15960565.
- Montgomery, P; Richardson, AJ; Depression, Anxiety and Neurosis Group (2008). "Omega-3 fatty acids for bipolar disorder". Cochrane Database of Systematic Reviews (2): CD005169. doi:10.1002/14651858.CD005169.pub2. PMID 18425912.
- Reynolds, Gretchen. "Prescribing Exercise to Treat Depression". The New York Times. Retrieved April 29, 2013.
- Small, J. G.; Milstein. V.; Klapper, M. H. (1986). "Electroconvulsive therapy in the treatment of manic episodes". Annals of the New York Academy of Sciences 426: 37–49. Bibcode:1986NYASA.462...37S. doi:10.1111/j.1749-6632.1986.tb51237.x.
- MacQueen, G.; Parkin, C.; Marriott, M.; Bégin, H.; Hasey, G. (2007). "The long-term impact of treatment with electroconvulsive therapy on discrete memory systems in patients with bipolar disorder". Journal of psychiatry & neuroscience 32 (4): 241–9. PMC 1911194. PMID 17653292.
- El-Mallakh, R. S.; Paskitti, M. E. (2001). "The ketogenic diet may have mood-stabilizing properties". Medical Hypotheses 57 (6): 724–6. doi:10.1054/mehy.2001.1446. PMID 11918434.
- Phelps, James R., Susan V. Siemers, and Rif S. El-Mallakh. "The ketogenic diet for type II bipolar disorder." Neurocase ahead-of-print (2012): 1-4.
- http://psychiatry.stanford.edu/research/bipolar.html[full citation needed]
- D'Souza,D.C., Abi-Saab,W.M., Madonick,S., Forselius-Bielen,K., Doersch,A., Braley,G., Gueorguieva,R., Cooper,T.B. and Krystal,J.H., 2005. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 57, 594-608.
- Ranganathan, Mohini; d'Souza, Deepak Cyril (2006). "The acute effects of cannabinoids on memory in humans: A review". Psychopharmacology 188 (4): 425–44. doi:10.1007/s00213-006-0508-y. PMID 17019571.
- Grotenhermen, Franjo (2007). "The Toxicology of Cannabis and Cannabis Prohibition". Chemistry & Biodiversity 4 (8): 1744–69. doi:10.1002/cbdv.200790151. PMID 17712818.
- Mann, Robert E.; Stoduto, Gina; Macdonald, Scott; Brands, Bruna (2008). "Cannabis use and driving: implications for public health and transport policy" (PDF). In Sznitman, Sharon Rödner; Olsson, Börje; Room, Robin. A cannabis reader: global issues and local experiences, Volume 2. pp. 173–98. doi:10.2810/15648. ISBN 978-92-9168-312-3.
- Lagerberg TV, Sundet K, Aminoff SR, Berg AO, Ringen PA, Andreassen OA, et al. Excessive cannabis use is associated with earlier age at onset in bipolar disorder. European Archives of Psychiatry Clinical Neuroscience 2011 Sep;261(6):397-405
- Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Research 2011 Apr 30;186(2-3):159-64)
- Tohen M, Vieta E, Gonzalez-Pinto A, Reed C, Lin D. Baseline characteristics and outcomes in patients with first episode or multiple episodes of acute mania. Journal of Clinical Psychiatry 2010 Mar;71(3):255-61.
- Strakowski SM, DelBello MP, Fleck DE, Arndt S. The impact of substance abuse on the course of bipolar disorder. Biological Psychiatry 2000 Sep 15;48(6):477-85.
- Baethge C, Hennen J, Khalsa HM, Salvatore P, Tohen M, Baldessarini RJ. Sequencing of substance use and affective morbidity in 166 first-episode bipolar I disorder patients. Bipolar Disorder 2008 Sep;10(6):738-41.
- Henquet C, Krabbendam L, de Graaf R, Ten Have M, Van Os J. Cannabis use and expression of mania in the general population. Journal of Affective Disorder 2006 Oct;95(1-3):103-10.
- Lagerberg TV, Kvitland LR, Aminoff SR, Aas M, Ringen PA, Andreassen OA, et al. Indications of a dose-response relationship between cannabis use and age at onset in bipolar disorder. Psychiatry Research 2013 Oct 30.
- De Hert M., Wampers M, Jendricko T, Franic T, Vidovic D, De VN, et al. Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophrenia Research 2011 Mar;126(1-3):270-6.
- International Society for Bipolar Disorders
- Mitchell, P. B.; Malhi, G. S.; Ball, J. R. (2004). "Major advances in bipolar disorder". Medical Journal of Australia 181 (4): 207–210. PMID 15310256.
- "Bipolar Family Treatment Center" Helping patients and families affected by Bipolar Mood Disorder, Associated with Beth Israel Medical Center in New York City
- Guzman, F. "Video Lecture: First and Second Generation Antipsychotics for the Treatment of Bipolar Disorder". Psychopharmacology Institute. Retrieved 2012-08-04.