The Role of Polypharmacy in Bipolar Disorder Treatment Guidelines

Guidelines for the recognition and management of mixed depression

“… Antidepressant monotherapy should probably NOT be utilized for patients with mixed depression of any type (unipolar, BP II, or BP I), given persisting doubts about the relative efficacy of standard antidepressants in treating bipolar disorders and their potential to destabilize mood 7 , 8 , 11 , 12 , 25 , 32 , 57 – 68 It is critical that patients presenting with a major depressive episode be assessed for the presence of any symptoms of (hypo)mania and family history of mood disorder, including bipolar disorder, before initiating treatment Patients with mixed depression should be monitored regularly for the emergence or worsening of (hypo)mania and suicidality Tricyclic antidepressants (TCAs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) may carry the highest risk of causing a treatment-emergent affective switch, 11 , 17 , 30 , 62 , 63 , 69 – 73 while bupropion and some selective serotonin reuptake inhibitors (SSRIs) may have a lower risk of affective switch There is some evidence for the adjunctive use of monoamine oxidase inhibitors in the treatment of bipolar depression 74 , 75 For symptomatic patients with mixed depression, antidepressant monotherapy should generally be tapered and discontinued. Clinicians should carefully assess whether mixed features may be exacerbated by antidepressant monotherapies; in such instances, consideration should be given either to augmentation with an atypical antipsychotic or antimanic mood stabilizer (e.g., lithium, divalproex, carbamazepine) or else tapering and discontinuing antidepressants altogether if deemed ineffective There are currently no psychotropic agents that are FDA- or EMA-approved for the treatment of depression with mixed features First-generation antipsychotics and sedatives (benzodiazepines, hypnotics) have been used successfully in the treatment of depressive mixed states Atypical antipsychotics (including asenapine, 76 , 77 lurasidone, 78 , 79 olanzapine, 80 quetiapine, 81 and ziprasidone 82 ) are the only psychotropic agents that have been specifically tested (and shown some efficacy) for the treatment of depression with mixed features Not all atypical antipsychotics have demonstrated efficacy in bipolar depression (e.g., Lombardo et al ., 2009 83 ).…”

“…There is some evidence for the adjunctive use of monoamine oxidase inhibitors in the treatment of bipolar depression 74 , 75 …”

“… The treatment of DMX may require a combination of medications 15 , 18 , 60 , 74 , 88 Combinations with potential efficacy in DMX: Atypical antipsychotic + mood stabilizer Atypical antipsychotic + antidepressant Olanzapine/fluoxetine combination in particular (caution in overweight or obese patients and those with metabolic dysregulation) Mood stabilizer + antidepressant If an antidepressant is prescribed for DMX, it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer); however, it is questionable whether adding an antidepressant to a mood stabilizer or atypical antipsychotic has therapeutic benefit in bipolar disorder patients 89 (Hypo)manic symptoms, irritability, dysphoric mood, and insomnia can deteriorate or develop during antidepressant treatment even in conjunction with mood-stabilizing agents 89 , 90 The role of antidepressants in long-term treatment is controversial and not established by controlled trials in DMX, but they may be used effectively in a small minority of patients in the long term, 11 particularly if there is a robust initial response or remission without signs of mood destabilization 91 The combination of olanzapine or risperidone with carbamazepine is not recommended due to potent pharmacokinetic induction of cytochrome P450 enzymes by carbamazepine 15 The use of additional short-term medication (e.g., benzodiazepines) may be necessary when an acute stressor is imminent or present, early symptoms of relapse (especially insomnia) occur, or anxiety becomes prominent Addition of hypnotics for the treatment of insomnia unresponsive to mood disorder medications may be helpful/necessary Higher doses of the long-term treatments may also be effective, thus avoiding the need for additional medications Ensure adequate doses of medicines and that serum levels of lithium and valproate are within the therapeutic range Address use of alcohol or illicit psychoactive substances that can destabilize mood Address current stressors; consider psychosocial interventions in general, particularly those targeting lifestyle/daily rhythms, e.g., interpersonal social rhythm therapy (IPSRT) If the patient fails to respond to optimization of long-term treatment, consider augmentation or change of treatment 9 , 11 , 12 , 17 There are some limited data supporting the adjunctive use of L-thyroxine, 92 , 93 N-acetyl-cysteine (NAC), 94 , 95 omega-3 fatty acids, 96 ramelteon, 97 celecoxib, 98 modafinil, 99 , 100 inositol, 101 , 102 ketamine, 103 , …”

“…The treatment of DMX may require a combination of medications 15 , 18 , 60 , 74 , 88 Combinations with potential efficacy in DMX: Atypical antipsychotic + mood stabilizer Atypical antipsychotic + antidepressant Olanzapine/fluoxetine combination in particular (caution in overweight or obese patients and those with metabolic dysregulation) Mood stabilizer + antidepressant If an antidepressant is prescribed for DMX, it should be used in conjunction with a mood-stabilizing agent (atypical antipsychotic or mood stabilizer); however, it is questionable whether adding an antidepressant to a mood stabilizer or atypical antipsychotic has therapeutic benefit in bipolar disorder patients 89 (Hypo)manic symptoms, irritability, dysphoric mood, and insomnia can deteriorate or develop during antidepressant treatment even in conjunction with mood-stabilizing agents 89 , 90 The role of antidepressants in long-term treatment is controversial and not established by controlled trials in DMX, but they may be used effectively in a small minority of patients in the long term, 11 particularly if there is a robust initial response or remission without signs of mood destabilization 91 The combination of olanzapine or risperidone with carbamazepine is not recommended due to potent pharmacokinetic induction of cytochrome P450 enzymes by carbamazepine 15 …”

“…Transcranial magnetic stimulation (TMS) may also have some efficacy in treating mixed depression; however, this supposition is based on “off-label” data from preliminary trials in bipolar depression; attempt TMS only after other options have been tried 74 …”