By Professor Ya Mei Bai, M.D, Ph.D. 

         Bipolar disorder is an important mental disorder with mood lability. The international prevalence is 1% for type I, and 1.1% for type II. ¹ In Taiwan, the prevalence of bipolar disorder was increased from 0.06% in 1996 to 0.4% in 2003 by the Taiwan National Health Insurance Research Database, ^2-4 there should be many patients, who were not recognized and treated. Bipolar disorder has different phases, and the pharmacological treatment is complicated, updated frequently with new research evidences.

1. The manic phase

   Although less than 10% of patients in acute mania received monotherapy treatment and some research evidences showed better efficacy of combination use of atypical antipsychotics and mood stablizers than monotherpay, the WFSBP guideline still suggest that clinicans need to try to maximize the efficacy of montherpay to avoid side effecs and risk of combination therapy, which are reserved for patients with severe symptoms, or as the subsequent treatment after failure of initial therapy.⁵

    

   Monotherapy for the manic phase

1. The classical mood stablizers, lithium, valproate, and carbamazepine, are all with good research evidence. For dysphoric or mixed mainia, valproate may have better efficacy than lithium. Carbamazepine may have better efficacy than lithium for dysphoric and mixed type of mania. But because of its tolerability and drug- drug interaction, it is listed as the second line recommondation.  Genotyping HLA-B-1502 has been suggested to reduce the risk of Steven-Johnson Syndrome.
2. The atypical antipsychotic drugs (second generation antipsychotic drugs), such as aripiprazole, olanzapine, quetiapine, risperidone, and zprasidone, are all with good research evidence, and may have better efficacy for dysphoric/mixed/ psychotic manic episodes than lithium.  Olanzapine has more adverse effects of weight gain and metabolic symptoms. A head-to-head comparison study showed that haloperidol can control of manic symptoms more quickly than quetiapine. Some other research studies suggested higher dose of quetiapine may have better response, but it was inconclusive. Taking ziprasidone with high caloric meal can increase the efficacy.
3. Other atypical antipsychotic drugs:  Paliperidone is the active metabolite of risperidone, with better efficacy with dose 12 mg/day is B. Although amisulpride is frequently used in clinical practice, only one randomized study with combination of valproate  showed  the comparable efficacy of amisulpride to haloperidol. Higher dose of amisulpride may be required for acute mania, but has the risk of hyperprolactinemia.  Clozapine showed efficacy for refractory mania in several open trials, but is limited to the patients with poor response to other antipsychotics treatment, because of the side effects.  Several small studies showed the efficacy of zotepine for acute mania, with side effects of sedation and extrapyramidal symptoms (EPS).

   4. Conventional antipsychotic drugs (typical antipsychotic drugs, or first generation antipsychotic drugs):  Although the tolerance issue is concerned, they still have an important role for acute mania with excitement or violence. The conventional antipsychotic, especially with high dose, may exacerbate dysphoric or depressed mood. A randomized placebo controlled study showed efficacy of chlorpromazine for acute mania with comparable efficacy with lithium. From the analysis of Taiwan national health insurance dataset, other conventional antipsychotics are frequently prescribed, including sulpiride (Dogmatyl), clothiapine (Etumine), fluphenazine (Modecate), flupenthixol (Fluanxol), loxapine (Rosup), thioridazine (Melleril), and trifluoperazine (Stelazine). 

   5. Electroconvulsive treatment (ECT) can be used for patients with poor response to other treatments, or under some special conditions, such as pregnancy.  The results from chart review and case reports have shown comparable efficacy of ECT with lithium and some kinds of antipsychotics in acute mania. The response rate is up to 80%. The repetitive transcranial magnetic stimulation (rTMS) may be a substitute for ECT. However, a single blind study did not show comparable efficacy.

   Combination/augmentation or adjunctive/add-on treatment for the manic phase

1. The reseach evidence has shown the combination therapy of lithium and divalproex had 1.5 fold efficacy than the monotherapy of either one. Combined lithium or divalproexwith atypical antipsychtoics also has better efficacy than monotherapy of lithium or divalproex.           
2. The research evidence has demonstrated no benefit of combined olanzapine with carbamazepine and may increase the risk of dyslipidemia and weight gain. The combination was not recommended.

    

1. The Depressive phase.

          

   Monotherapy for the depressive phase
    

1. Only quetiapine is with good research evidence. The research evidence have confirmed the efficacy of quetiapine monotherapy for the depressive episodes, with better efficacy than lithium monotherapy, paroxetine and placebo to improve the depressive symptoms and the remission rate. But the tolerability and long-term safety need to be concerned.  
2. Lamotrigine is not approved by USA FDA for the depressive phase use.  However, it was approved by the Taiwan DOH for the indication of bipolar depressive phase. Due to the side effects of lamotrigine such as skin rash, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), the administration of lamotrigine should be started with low dose, slow titration, and required close monitoring.
3. There were no good evidence of valproate for depressive phase, but was widely prescribed, and approved by Taiwan DOH. The side effects of weight gain, hair loss, teratogenicity and polycystic ovarian syndrome need to be concerned.
4. The research evidence of lithium for depressive episode is inconsistent, but widely used in Taiwan. There is still no Taiwan empirical data to account for.
5. Two studies of olanzapine combined with fluoxetine showed positive results for bipolar depressive episode. However, the efficacy of olanzapine monotherapy is still inconclusive and weight gain and metabolic side effects need concern.
6. The research evidence of carbamazepine for the depressive episode is inconclusive.

      Combination/augmentation or Adjunctive/add-on Treatment for the Depressive Phase

1. Combination therapy of lithium and valproate/lamotrigine is the first line approach in many treatment guidelines for the better efficacy than montherapy.     Of concerns is that more side effects may occur with this combination therapy, especially for the central neural system and skin.
2. Antidepressants are frequently prescribed for depressive episode use, but the studies are limited with small sample sizes or short study period. The best evidence is from combination of olanzapine and fluoxetine, but weight gain and metabolic side effects need concern. Some open trials have shown positive results of quetiapine combined with SSRI. Nonetheless, the evidence for the combination of lithium (or valproate) with antidepressants (sertraline/paroxetine /bupropion) is inconsistent. The analysis of Taiwan national health insurance showed sulpiride has been widely used for the depressive episode. One double-blind study showed that sulpiride has equivalent antidepressant activity to amitriptyline with faster onset at the first week of trial, and fewer side effects than amitriptyline..

1. The Maintenance phase

    

   Monotherapy for maintenance Phase
    

1. All the three mood stabizers, lithium, valproic acid, and lamotrigine, are with good research evidence.  But lithium has more side effects and two-fold risk of discontinuation compared to the other two mood stablizers.  Another mood stablizer, carbamazepine is with moderate resech evidence, with less risk of weight gain, and the issue of skin allergy receiving less concerns during the maintenance phase,
2. Four atypical antipyschotics, olanzapine, quetiapine, long-acting risperidone injection (RLAI), and aripiprazole, are all with good research evidence, but with side effects of weight gain, and less efficacy of preventing depressive episodes.

    

   Combination/augmentation or adjunctive/add-on therapy for the maintenance phase
   1. Combination therapy with lithium/valproic acid and quetiapine may have better efficay      

   than monotherapy, but may also have more side effects of weight gain and metabolic
   syndrome.

   2. Combination therapy with lithium, divalproex and carbamazepine is commonly seen in clinical psychiatric practice.

   3. The research evidence confirmed the combination therapy with lithium/divalproex, lithium or valproic acid with risperidone long-acting injection ,ziprasidone, and with aripiprazole, but with less efficacy for preventing depressive episodes.

   4. Combination of lithium with olanzapine/risperidone/ lamotrigine, are all moderate reserch evidence, and the adverse effects of weight gain and metabolic syndrome need to be concerned.

   5. Open trials have shown clozapine montherapy or combined with other treatments can improve symptoms and prevent rehospitalization . The side effects of weight gain and metabolic syndrome need concerns. 

   6. Adjunctive treatment with topiramate, oxcarbazepine, and gabapentin, are all with incosistent results. Topiramate may reduce body weight.

    

   The role of antidepressants in the maintenance phase
   The role of antidepressants in the maintenance phase therapy is still debatable, although more than 50% of patients have residual depressive symptoms. The research evidence about the risk of switching to mania with antidepressants is inconsistent. Only limited evidence has supported that antidepressants can prolong the remission period of depression. Most studies have suggested that the antidepressants can be only used in combination of mood stabilizers; otherwise, the risk of mania switch will be increased. In addition, the combination of antidepressants with mood stablizers is only suggested for patients with type II bipolar disorder because higher risk of switching to mania has been reported with type I bipolar disorder. The drug-induced mania switch occurs especially with receiving a tricyclic antidepressant (TCA) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

    

   Pharmacotherpay combined with psychosocial intervention will improve the treatment efficacy

    

   The non-pharmacological, psychoocial intervention is important to the successful treatment of pharmacotherapy. The psychoeducation can improve patients’ insight, facilitae understanding the impact of bipolar disorder, and have self-monitoring, self-regulation, and improve adherence to medications.⁷ Other treatment modalities including group psychotherapy, cognitive behaviour therapy, interpersonal and social rhythm therapy, and family-focused therapy are also observed to reduce the relapsae rate and improve medication adherence.