Figure_1111.pngBipolar disorder is a type of mood disorder that manifests as repeated cycles of depression and mania. It has a prevalence of 1-5%[1] in North America, making further development of new and pre-existing treatments for bipolar disorder crucial. There are many effective psychotherapies and pharmacological treatments that exist to help those affected by this disorder, but evidence shows that the most successful outcomes occur with a combination of both medication and therapy[2] . Medications include Lithium, anticonvulsants, and antidepressants while therapies include behavioural, interpersonal, and/or cognitive therapy. Figure 1[3] represents the prevalence of pharmaceutical medications used for the treatment of bipolar disorder. Treated patients live longer symptom-free lives, have lower rates of relapse, and are at a much lower risk of suicide then those who do not seek the necessary aid.

Other more unconventional treatments that have been shown to be effective include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and vagus nerve stimulation (VNS). These treatments aim to provide relief to patients by directly stimulating or inhibiting affected brain area that may be over-active or under-active in these individuals.

Pharmacological Treatments:

Pharmacological treatments are treatments that involve the use of medication and drugs.


Discovered in the 1950’s, lithium is considered the most effective first-line treatment for bipolar disorder and remains one of the most highly prescribed pharmaceuticals for the management of bipolar disorder Figure 2[4] represents the different phases of bipolar disorder and the type of medication prescribed for each phase, notably lithium as the first line prescription for all stages of bipolar disorder. Most predominantly, lithium is associated with successfully preventing relapse, decreasing suicide rates, and reducing dementia. However, it causes many negative side effects including weight gain, nausea, and has a very narrow threshold from being effective to being toxic. Although many opt out of using lithium, its effectiveness in treating and managing long-term bipolar disorder has not been surpassed.
Lithium involves stabilizing moods and emotions by acting on the neurotransmitters glutamate, dopamine and GABA[5] . Studies conducted by Hokin et al., suggest that lithium increases the availability of glutamate and GABA, while decreasing dopamine levels in the pre-synaptic regions[6] [7]

Equally as important as its effectiveness is lithium’s ability to decrease incidences of relapse in those affected. A meta-analysis conducted by Geddes et al. in 2004 found that patients taking lithium had an overall decrease in relapse from 61% to 40%[8] . Additionally, patients who are on lithium reported a lower number of suicidal thoughts and showed fewer self-harming behaviors then those on a placebo or no medication. Typically, patients with bipolar disorder are at 10 time greater risk of committing suicide than the average person[9] . A review article by Baldessarini et al. connects to earlier findings by Muller- Oerlinghausen, showing on average that suicide attempts in patients using lithium was reduced by 82%-85%[10] [11] . Other related research saw lithium reduce the risk of suicide and self-injury by 60%-70%[12] . Finally, researchers have identified a negative correlation between lithium use and dementia, patients using lithium for an extended period had reduced rates of dementia, as compared to those on antipsychotics, antidepressants and/or anticonvulsants[13] .

Despite the usefulness of lithium, its negative effects are sometimes life threatening and cause more damage than help. Research conducted by Johnston and Eagles demonstrated that treatment with lithium increases the incident rate of transient subclinical hypothyroidism in 10% of all patients. In females this rate is approximately 13%, while people between the ages of 40 – 60 are at an even greater disadvantage, having an incident rate of nearly 20% [14] . Similarly, lithium causes a reduction in the kidney’s function to store water and concentrate urine, which has been shown to increase the risk of developing diabetes [15] . Furthermore, lithium usage increases the incidence of “nausea, dry mouth, tremor, constipation and diarrhea” and can cause birth defects if taken in the first trimester of pregnancy[16] . Although lithium may benefit many patients with bipolar disorder and can reduce suicide rates, overall lithium has a small window between being beneficial and toxic and many patients do not want to risk the chance of these adverse effects.


Anticonvulsants are primarily used for treating convulsion as a result of seizures, but have been shown to also be affective as a second-line treatments for bipolar disorder patients suffering from manic episodes. They are the prescribed alternative when lithium fails, or for patients who cannot tolerate the side effects attributed to lithium. Similar to lithium, patients prescribed anticonvulsants had reduced suicidal and self-harming thoughts. Research conducted by Gibbons et al. at the University of Illinois determined that suicide rates of patients using anticonvulsants were dramatically reduced when compared to pre-treatment or no medication treatments of bipolar disorder patients[17] The type of anticonvulsant medication prescribed also affected the rate of suicide (Figure 3[18] ). Additionally, over time, there were reduced suicide attempts in patients prescribed anticonvulsants, compared to those given other medications (Figure 4[19] ). The most frequently prescribed anticonvulsants include valproate, lamotrigine and carbamazepine; these drugs can dramatically reduce the symptoms of mania or depression.firgure_4.png
                • Valproate (VPA):
Valproic acid, better known as valproate, is an effective pharmacological prescription for those suffering with manic symptoms. Research by Vasudev and others has shown that valproate works faster at relieving manic symptoms, when compared to lithium or carbamazepine[20] . Additionally, valproic acid has fewer adverse side effects, is more tolerable, and can reduce relapse when administered in high doses. However, with elevated dosage, the tolerability of valproic acid worsens and can cause weight gains, gastrointestinal problems and has been seen to lower white blood cell count [21] . Other side effects include hair loss, nausea, vomiting and dizziness, but since these effects are considered mild, many patients opt to use VPA over lithium or carbamazepine.
                      • Lamotrigine (LTG):
Although valproate is effective for the treatment of manic episodes, it has shown a reduced ability to treat depressive symptoms related to bipolar depression. Therefore other anticonvulsants such as lamotrigine are commonly prescribed. Research by Van der Loos and Goodwin demonstrated that lamotrigine had significant effectiveness as an antidepressant, and was successful in preventing relapse of depressive episodes[22] [23] . Additionally, patients on LTG experienced mild side effects, including headaches and weight loss, but were able to safely be on a cocktail of other medications. This drug does not seem to act synergistically with other drugs, which makes it less harmful than other anticonvulsants and a favorable choice for doctors and psychiatrists.
                      • Carbamazepine (CBZ):
Carbamzepine, sold by the trade name Tegretol, is an effective medication for those experiencing manic episodes and rapid cycling in bipolar disorder. In recent years, CBZ has become less prescribed by doctors and VPA becoming the alternative. This is largely due to the fact that carbamazepine works just as effectively as VPA but contains greater adverse side effects[24] . This side effects range from mild to life threatening and can include, “diplopia, uncoordination, sedation, weight gain…benign rash in as many as 1/3 of patients, hypersensitivity syndrome including features of Stevens Johnson syndrome (0.1–0.5 %), leucopenia 10-20%, and rarely aplastic anemia or agranulocytosis”[25] . Furthermore, increased cholesterol levels, nausea, blurred vision and liver disease have also been reported in patients using CBZ[26] . This makes carbamazepine a less desirable choice for treatment on manic episodes and it is only prescribed if lithium, VPA or other anticonvulsants are ineffective.

Atypical Antipsychotics

Second-generation antipsychotics, better known as, atypical antipsychotics are primarily prescribed to patients with acute mania who exhibit symptoms that impair everyday function. Antipsychotics are usually used for treating schizophrenia, but can also used as add-on medications in bipolar disorder. These drugs have both mood stabilizing and antidepressant activities, making them a favorite for treating both the manic and depressive cycles of bipolar disorder[27] . Antipsychotics are used by 53 percent of bipolar disorder patients and this class of medication is most commonly prescribed as an additional treatment to help with mood stabilizing [28] . Atypical antipsychotics differ from typical antipsychotics in that they produce less adverse side effects, most importantly lowering the risk of tardive dyskinesia[29] . Additionally, atypical antipsychotics have also been shown to improvTable_1.pnge cognition and decrease the risk of suicide.

The first atypical antipsychotic produced was clozapine, which was found to be quite effective at alleviating manic episodes. Research by Suppes et al. found that patients treated with clozapine had considerable improvements in their manic episodes compared to those not prescribed antipsychotics[30] . Additionally, patients using clozapine remain stable and do not relapse for longer periods of time. Other prescribed antipsychotics include olanzapine and risperidone, both of which decrease the incidence of manic and depressive episodes in patients with bipolar disorder[31] . Side effects of antipsychotics include weight gain, sedation, agranulocytosis, and decreased sexual drive. Table 1[32] illustrates the side effects associated with atypical antipsychotics and their relative contributions to these effects. All in all, atypical antipsychotic drugs are especially important for cases where manic episodes produce psychotic tendencies, such as perceptional hallucinations, which make the patient a danger to themselves and others.


Antidepressants are a class of prescription medication that helps to alleviate symptoms of depression and stabilize mood. They are prescribed as an add-on treatment 85% of the time, or used when lithium and/or atypical antipsychotics have failed to relieve depression[33] . Interestingly, research conducted by Gheami et al. revealed that antidepressants were prescribed to 80% of patients with bipolar disorder over their lifetime, while mood stabilizers were only given to around 50% of patients[34] . This implies that the use of antidepressants is crucial for dealing with depressive symptoms, even though there is speculation that they induce mania more frequently. Many researchers and psychiatrists have questioned whether the use of antidepressants increases the likelihood of cycling between manic and depressive states. Research by Gijsman et al. and Cipriani et al., however, revealed that there was no significant evidence for this claim[35] [36] . Additionally, it was discovered that the use of antidepressants did not improve recovery rates when combined with a mood stabilizer. Sachs et al., found that patients given a combination of antidepressant and mood stabilizer medication had equal – if not insignificantly lower – recovery rates then patients who were given a mood stabilizer and a placebo mixture. This reveals that antidepressant medication does not increase bipolar disorder recovery rates or the cycling between manic and depressive episodes[37] .

Most commonly prescribed antidepressants include tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). Use of MAOIs is linked to a number of restrictions and side effect. When used, patients are required to avoid tyramine-rich foods including red wine, chocolate and cheese since MAOIs can interact and cause increases in blood pressure. MAOIs can also cause weight gain and liver damage, symptoms similar to those seen when using tricyclic antidepressants[38] . Of all the antidepressants, SSRI seem to have the least amount of effects and are becoming the most commonly prescribed type of antidepressant. They alleviate symptoms of depression within a couple of weeks, and have a very high LD50 value[39] . However, patients on any antidepressant medication complain of having anxiety, sleep impairment, menstrual irregularity and irritability symptoms[40] . Overall, antidepressants should not be prescribed as a first line treatment for those suffering from bipolar depression but should be used in moderation and in combination with other treatments.

Electroconvulsive Therapy :

Electroconvulsive therapy (ECT), also known as shock therapy, is one of the most controversial treatments for bipolar disorder. Originally given as a treatment for schizophrenia, ECT is now used for patients suffering from severe depression and who are unresponsive to pharmaceuticals. Electroconvulsive therapy involves electric currents passing through one side on the brain and causing a generalized seizure and it is this convulsion that causes the antidepressant response. Patients prescribed ECT are anaesthetized before treatment commences and are typically required to have anywhere from 6 – 12 treatments. Research by Medda et al. showed that ECT reduced depressive symptoms and had response rates of 67%[41] . Additionally, the study revealed that ECT was considerably tolerable in most patients with only 3 patients stopping treatment because of adverse effects from the 90 patients recruited for the study[42] . Although electroconvulsive therapy is given only to patients who are severely depressed, many researchers argue that ECT should be considered a viable therapy and not a treatment given as a “last resort”[43] . Common side effects of ECT include cardiac complications and hypertension and cognitive adverse events including retrograde and anterograde amnesia[44] . Overall, although ECT can quickly alleviate depressive symptoms, relapse rates are considerably high and patients must continuously be treated with ECT to avoid recurrence of depressive symptoms.

Psychological therapy :

Psychological therapies are treatments that in use of talk thrapies to change a patient’s behaviour, cognition, and/or outlook on life. There are several types of therapies available for patients with bipolar disorder; one of which includes behaviour therapy. This type of therapy attempts to increase the number of positive experiences by changing a person’s interaction with his surroundings. Another type of therapy is Interpersonal therapy (IPT) which helps patients deal with the loss of family or friends – whether death or relationships. Additionally, psychodynamic therapy involves unraveling the source of depression through therapist client interaction. Finally, cognitive-behaviour therapy appears to be most effective and typically prescribed as the first type of therapy.

Cognitive-Behaviour Therapy:figure_5.jpg

Cognitive- Behaviour therapy or CBT is a blending of both cognitive and behavior therapies that aims to change maladaptive thought processes and distressful behaviours. It relies on the assumption that patients with bipolar disorder have dysfunctional attitudes and experience loss of control over their life. Therapists work with the patient over a 12-month interval to help set goals they want the patients to accomplish while in therapy. These goals include improving life skill management, and helping patients realize and cope with the fact that they have a disorder. Additionally, CBT attempts to educate patients about the effects and repercussions of Bipolar disorder and their options for treatment. They also encourage avoidance of environmental triggers that may aggravate the situation, and suggest possible techniques of relaxation and that may benefit their client.

Patients are encouraged to keep regular notation of their emotional experiences during regular periods outside of therapy, so that therapists are able to help them place the origin of their depressive or manic episode. Figure 5 represents an example of a personal journal records that a patient kept for therapeutic analysis. Research by Meyer and Hautzinger showed that CBT helps prevent depressive episodes while in therapy, decreases overall symptom levels and relapse rates after therapeutic intervals[45] . In a study by Lam et al., with 100 bipolar disorder patients, results showed that patients treated with CBT spent 110 fewer days with bipolar episodes, and had improved social functioning[46] . Overall, CBT is an effective add-on treatment to pharmacological medication and is useful especially when mood stabilizers are ineffective.

Physical treatment/ new research :

Repetitive transcranial magnetic stimulation (rTMS):

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment that uses magnetic manipulation to provoke firing of action potentials in various cortical regions. A brief electrical current is passed through a coil of wire that is placed on the scalp of a patient, which creates a high intensity magnetic field that can alter brain activity[47] . In bipolar and depressed patients there tends to be noticeably lower activation in the left prefrontal cortex, which contributes to symptoms such as anhedonia. Activation in this area by rTMS has been shown to increase the functioning of this cortical area, normalizing activity levels and thereby producing an antidepressant effect[48] . Since rTMS does not require anesthesia, side effects are usually mild, with headaches as the most common problem. Additionally, research by Cohen et al. discovered that rTMS is an effective substitute treatment for pregnant women who cannot take pharmacological medications because of their negative side effects[49] . Despite the positive acclaim that this relatively new treatment has received, because it is only applied to the cranium, it is limited to effecting cortical areas. Other more invasive techniques are needed in order to stimulate problem areas that are located in deeper subcortical regions.

Vagus nerve stimulation (VNS):

Vagus nerve stimulation (VNS) is direct biological method for treating severe depression. The vagus nerve is part of the autonomic nervous system, and is one of twelve pairs of cranial nerves in the body[50]. Stimulation of this nerve has been shown improve depressive symptoms, but researchers are unaware why this occurs[51]. PET scans suggest that it increases activity in the hypothalamus and amygdale[52]. This treatment is invasive however, requiring a small electronic device to be surgically implanted in the patient’s chest. Current research is still gathering evidence to determine the usefulness of this treatment for treating bipolar patient.
  1. ^ Emilien, G., Septien, L., Brisard, C., et al. (2007) Bipolar disorder: how far are we from a rigorous definition and effective management? Prog Neuropsychopharmacol Bio Psych 31: 975-996 (2007)
  2. ^ Heinz Grunze et. al. (2010) The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the treatment of acute bipolar depression. The World Journal of Biological Psychiatry 11: 81–109
  3. ^ Figure 1. Frequency of drugs prescribed to patients with Bipolar Disorder. Reprinted from “Treatment of Bipolar Disorder” by Ventimiglia J, Kalali AH and McIntyre RS Psychiatry 6(10): 12–15 (2009)
  4. ^ Figure 2. Summary of current treatments prescribed to patients with bipolar disorder. Reprinted from “The science and practise of lithium therapy.” by Gin SM, Tanious M, Das P, et al. Australian and New Zealand Journal of Psychiatry 46(3): 191–211 (2012)
  5. ^ Gin SM, Tanious M, Das P, et al. (2012) The science and practise of lithium therapy. Australian and New Zealand Journal of Psychiatry 46(3): 191–211
  6. ^ Hokin LE, Dixon JF and Los GV (1996) A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 triphosphate accumulation via activation of the N-methyl d-aspartate receptor in monkey and mouse cerebral cortex slices. Advances in Enzyme Regulation 36: 229–224
  7. ^ Post RM, Speer AM, Hough CJ, et al. (2003) Neurobiology of bipolar illness: implications for future study and therapeutics. Annals of Clinical Psychiatry 15: 85–94
  8. ^ Geddes JR, Burgess SB, Hawton K, et al. (2004) Long-Term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 161: 217–222
  9. ^ Baldessarini RJ, Tondo L, Davis P, et al. (2006) Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analysis review. Bipolar Disorders 8: 625–639
  10. ^ Baldessarini RJ, Tondo L, Davis P, et al. (2006) Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analysis review. Bipolar Disorders 8: 625–639
  11. ^ Miller-Oerlinghausen B, Muser-Causeemann B, and Volk J (1992) Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. Journal of Affective Disorders 25: 261–270
  12. ^ Cipriani A, Pretty H, Hawton K et. al (2005) Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorder: a systematic review of randomized trials. The American Journal of Psychiatry 162:1805–1819
  13. ^ Kessing LV, Forman JL and Andersen PK (2010) Does lithium protect against dementia? Bipolar Disorders 12: 87–94
  14. ^ Johnston AM and Eagles JM (1999) Lithium-associated clinical hypothyroidism: prevalence and risk factors. The British Journal of Psychiatry 175: 336-339
  15. ^ Gin SM, Tanious M, Das P, et al. (2012) The science and practise of lithium therapy. Australian and New Zealand Journal of Psychiatry 46(3): 191–211
  16. ^ Bowden CL, Mosolov S, Hranov L, et al. (2010) Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12- week trial. International Clinical Psychopharmacology 25: 60–67
  17. ^ Gibbons RD, Hur k, Brown H et al., (2009) Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 66(12): 1354–1360
  18. ^ Figure 3. Suicide attempt rates. Reprinted from “Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder,” by Gibbons RD, Hur k, Brown H et al., (2009) Arch Gen Psychiatry 66(12): 1356
  19. ^ Figure 4. Suicide rates over time. Reprinted from “Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder,” by Gibbons RD, Hur k, Brown H et al., (2009) Arch Gen Psychiatry 66(12): 1358
  20. ^ Vasudev K, Goswami U and Kohli K (2000) Carbazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder. Psychopharmacology 150: 15–23
  21. ^ Bowden CL, Calabrese JR, McElroy SL wt al., (2000) A randomized, placebo- controlled 12- month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Archives of General Psychiatry 57: 481–489
  22. ^ Van der Loos M, Mulder P, Hartong E et al., (2011) Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design. Bipolar Disorder 13: 111–117
  23. ^ Goodwin GM, Bowden CL, Calabrese JR et al., (2004) A pooled anaylsis of 2 placebo- controlled 18-month trials of lamotrigine and lithium maintenance I bipolar I disorder. Journal of Clinical Psychiatry 65: 432–441
  24. ^ Heinz C and Grunze R (2010) Anticonvulsants in bipolar disorder. Journal of Mental Health 19(2): 127–141
  25. ^ Bowden CL and Karren NU (2006) Anticonvulsants in bipolar disorder. Australian and New Zealand Journal of Psychiatry 40: 386–393
  26. ^ Nemeroff CB (2000) An ever-increasing pharmacopoeria for the management of patients with bipolar disorder. Journal of Clinical Psychiatry 61: 19–25
  27. ^ Angst J, Azorin JM, Bowden CL, et al. (2011) Prevalence and characteristics of undiagnosed bipolar disorder in patients with a major depressive episode. Arch Gen Psychiatry 68(8): 791–799
  28. ^ Ventimiglia J, Kalali AH and McIntyre RS (2009) Treatment of Bipolar Disorder. Psychiatry 6(10): 12–15
  29. ^ ]]
    Ertugrul A and Meltzer HY (2003) Antipsychotic drugs in bipolar disorder. International Journal of Neuropsychopharmacology 6: 277–284
  30. ^ Suppes T, Webb A, Paul B, et al., (1999) Clinical outcome in a randomized 1-year trail of clozapine verse treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry 156: 1164–1169
  31. ^ Fehr BS, Ozcan ME and Suppes T (2004) Low doses of clozapine may stabilize treatment- resistant bipolar patients. Eur Arch Psychiatry Clin Neurosci 255: 10–14
  32. ^ Table 1. Side effects associated with atypical antipsychotics. Reprinted from “Understanding psychiatric medications: Antipsychotics – information for consumers, families and friends” by CAMH: Center for Addiction and Mental Health (2009)
  33. ^ Cascade EF, Reites J, and Kalali AH (2007) Antidepressants in bipolar disorder. Psychiatry 56–58
  34. ^ Ghaemi SN, Boiman EE and Goodwin FK (2000) Diagnosing bipolar disorder and the effects of antidepressants: a naturalistic study. J Clin Psychiatry 61(10): 804–808
  35. ^ Gijsman HJ, Geddes JR, Rendell JM, et al. (2004) Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry 161: 1537– 1547
  36. ^ Cipriani A and Geddes JR (2008) Antidepressants for bipolar disorder: a clinical overview if efficacy and safety. Psychiatric Times 25(7): 36–41
  37. ^ Sachs GS, Nierenberg AA, Calabrese JR, et al. (2007) Effectiveness of adjunctive antidepressant treatment for bipolar depression. The New England Journal of Medicine 356(17): 1711–1722
  38. ^ Gillman PK (2007) Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology 151: 737–748
  39. ^ Nemeroff CJ and Schatzberg AF (1998) Pharmacological treatment of unipolar depression. A Guide to Treatments that Work 212–215
  40. ^ Fave GA and Offidana E (2010) The mechanisms of tolerance in antidepressant action. Progress in Neuro-Psychopharmacology & Biological Psychiatry 35: 1593–1602
  41. ^ Medda P, Perugi G, Zanello S, et al. (2010) Comparative response to electroconvulsive therapy in medication-resistant bipolar I patients with depression and mixed state. Journal of ECT 26(2): 82–86
  42. ^ Medda P, Perugi G, Zanello S, et al. (2010) Comparative response to electroconvulsive therapy in medication-resistant bipolar I patients with depression and mixed state. Journal of ECT 26(2): 82–86
  43. ^ Minnai GP, Salis PG, Oppo R, et al. (2011) Effectiveness of maintenance electroconvulsive therapy in rapid-cycling bipolar disorder. Journal of ECT 27(2): 123–126
  44. ^ Sackeim HA, Dillingham EM, Prudic J, et al., (2009) Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes. Arch Gen Psychiatry 66(7): 729–37
  45. ^ Meyer TD and Hautzinger M (2011) Cognitive behaviour therapy and supportive therapy for bipolar disorders: relapse rates for treatment period and 2-year follow-up. Psychological Medicine 1–11
  46. ^ Lam DH, Hayward P, Watkins ER, et al. (2005) Relapse prevention is patients with bipolar disorder: cognitive therapy outcome after 2 years. Am J Psychiatry 162: 324–329
  47. ^ Nahas Z, Molloy MA, Hughes PL, et al. (1999) Repetitive transcranial magnetic stimulation: perspectives for application in the treatment of bipolar and unipolar disorders. Bipolar Disorder 2: 73–80
  48. ^ George MS, Lisanby SH, Avery D, et al. (2010) Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. Arch Gen Psychiatry 67(5): 507–516
  49. ^ Cohen RB, Ferreira MS, Ferreira MJL, et al. (2008) Use of repetitive transcranial magnetic stimulation for the management of bipolar disorder during the postpartum period. Brain Stimulation 1: 224–226
  50. ^ Rush AJ, Marangell LB, Sackeim HA, et al (2005) Vagus nerve stimulation for treatment- resistant depression: a randomized, controlled. Biol Psychiatry 58:347–354
  51. ^ George MS, Rush AJ, Marangell LB (2005) A one- year comparison of vagus nerve stimulation with treatment as usual for treatment- resistant depression. Biol Psychiatry 58(5): 364–373
  52. ^ George M, Sackeim HA, Marangell LB (2000) Vagus nerve stimulation: a potential therapy for resistant depression? Psychiatric Clinics of North America 23: 757–783