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.

Lithium

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.
figure_2.png
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.

Anticonvulsantsfigure_3.png

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.

Antidepressant

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.
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