Treatment of bipolar disorder

Source: Wikipedia, the free encyclopedia.

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.[1] 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, and in the hippocampus, which is essential for storing memories. It has been shown that patients with bipolar disorder have less total brain volume, grey and white matter, and more cerebral spinal fluid.[2]

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.[3] 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%.[4] 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.[4] Treatment setting should regularly be re-evaluated to ensure that it is optimal for the patient's needs.

Mood stabilisers[5][6][7][8]
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:
B3 (Au)
C (US)		 Oral, Intramuscular
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,
dysmenorrhoea, rhinitis
, pain
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 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:

D (Au)
D (US)
Risk of Epstein's anomaly and other congenital heart defects.[9][10]

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:

C (Au) C (US)

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:

B3 (Au) C (US)

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:

B3 (Au) C (US)

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:

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 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:

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

Drug[8][11] 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)
Asenapine Yes No No Yes No Yes Yes No No
Carbamazepine Yes No No No No Yes No No Yes
Cariprazine Yes Yes[12] No
Haloperidol No No No Yes No No No No No
Lamotrigine No No Yes No No Yes No No Yes (depressive episodes)
Lithium Yes No Yes Yes No Yes Yes No Yes
Olanzapine Yes No (yes when in conjunction with fluoxetine) Yes Yes No Yes (as an adjunct to valproate/lithium) Yes No No
Quetiapine Yes Yes Yes Yes Yes Yes Yes Yes Yes
Lurasidone Yes
Risperidone Yes No Yes Yes No Yes Yes No No
Valproate Yes No No No No Yes Yes No Yes
Ziprasidone Yes No No (yes as adjunct) Yes No No No No No
Zuclopenthixol No No No Yes No No No No No

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.[13] 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

bipolar depression, although the evidence is not as strong.[3] It is also effective in reducing the risk of suicide in patients with mood disorders.[14]

Potential side effects from

acute mania.[15]

Lithium levels should be above 0.6 mEq/L to reduce both manic and depressive episodes in patients.[16] 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.[17]

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.[4]

Anticonvulsants

A number of

depressive episodes.[18]

acute mania.[3]

Zonisamide (trade name Zonegran), another anti-convulsant, also may show promise in treating bipolar depression.[19] Various other anti-convulsants have been tested in bipolar disorder, but there is little evidence of their effectiveness.[3] Other anti-convulsants effective in some cases and being studied closer include phenytoin, levetiracetam, pregabalin and valnoctamide.[20]

Each anti-convulsant agent has a unique side-effect profile.

divalproex, which is available in an enteric-coated tablet.[3] These side effects tend to disappear over time.[4] 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.[4]

Side effects of

blood cell counts are recommended.[4]

exfoliative dermatitis.[3]

Atypical antipsychotic drugs

Antipsychotics work best in the manic phase of bipolar disorder.[21] Second-generation or

glutamate activity. Several studies have shown atypical antipsychotics to be effective both as single-agent and adjunctive treatments.[22] Antidepressant effectiveness varies, which may be related to different serotonergic and dopaminergic receptor binding profiles.[3] Quetiapine and the combination of olanzapine and fluoxetine have both demonstrated effectiveness in bipolar depression.[22]

In light of recent evidence,

prophylaxis.[24]

The

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.[25]

New treatments

A variety of other agents have been tried in bipolar disorder, including

ALS has been studied as an adjunct or monotherapy treatment in bipolar depression, with mixed and inconsistent results.[28][29][30][31] The selective estrogen receptor modulator medication tamoxifen has shown rapid and robust efficacy treating acute mania in bipolar patients.[32][33][34][35] 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.[32]

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.[36] 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.[37]

Although decreased verbal memory and slowed psychomotor speed are common side effects of lithium use[38][39] 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.[40]

Antidepressants

Antidepressants are used with caution in bipolar disorder, as they may not be effective and may even induce mania.[3] They are generally not used alone, but may be considered as an adjunct to lithium.[4]

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.[41]

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.

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.[44]
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.[45]

NMDA-receptor antagonists

In a

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.[47]

Ketamine is used as 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 greater than in the control group.[48]

Psychotherapy

Main article: Psychotherapy

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.[49] Evidence of the efficacy of family therapy is not adequate to support unrestricted recommendation of its use.[50] There is "fair support" for the utility of cognitive therapy. Evidence for the efficacy of other psychotherapies is absent or weak,[51] often not being performed under randomized and controlled conditions.[52] Well-designed[52] studies have found interpersonal and social rhythm therapy to be effective.[53]

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 therapy

Jungian authors have likened the

mental imagery."[54][55][56][57][58][59]

Lifestyle changes

Sufficient sleep

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 by psychiatric authorities to not sleep too late and to get enough high quality sleep. [61]

Self-management and self-awareness

Understanding the symptoms, when they occur and ways to control them using appropriate medications and psychotherapy generally helps those diagnosed with bipolar disorder to lead a psychologically healthier life. Prodrome symptom detection has been shown to be used effectively to anticipate onset of manic episodes[62][63] and requires close monitoring of bipolar symptoms. Because the offset of the symptoms is often gradual, even subtle mood changes and activity levels are monitored to help avoid a relapse.[64] Maintaining a mood chart[65] is a specific method used by patients and doctors to identify mood, environmental and activity triggers.[66]

Stress reduction

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.[citation needed]

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.[67]

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,[68][69][70] and may impair the ability to safely operate a motor vehicle.[71]

Cannabis use is common in bipolar disorder;[72][73] and is a risk factor for a more severe course of the disease by increasing frequency and duration of episodes.[74][75][76][77] It is also reported to reduce age at onset.[78][79]

Other treatments

Omega-3 fatty acids

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,

GERD—food sources may be a good alternative in such cases.)[80]

Exercise

Exercise has also been shown to have antidepressant effects.[81]

Electroconvulsive therapy

Main article: Electroconvulsive therapy

Electroconvulsive therapy (ECT) may have some effectiveness in mixed mania states, and good effectiveness in bipolar depression, particularly in the presence of psychosis.[4] It may also be useful in the treatment of severe mania that is non-responsive to medications.[82][83]

The most frequent side effects of ECT include

muscle aches.[15] In some instances, ECT can produce significant and long-lasting cognitive impairment, including anterograde amnesia, and retrograde amnesia.[84]

Ketogenic diet

Because many of the medications that are effective in treating epilepsy are also effective as mood stabilizers, it has been suggested that 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.

See also

References

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Further reading

External links

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