Personalized Pharmacotherapy for Bipolar Disorder: How to Tailor Findings From Randomized Trials to Individual Patient-Level Outcomes
Abstract
Abstract
Translating Randomized Trials to Individualized Care
Moderators and Mediators of Treatment Outcome
Moderator | Relevance |
---|---|
Age at onset | Early onset (prepubertal, adolescent) is one of the more robust correlates of poor outcome, although it sometimes may be a proxy variable for more immediate causes of poor outcome (e.g., social isolation or poorer premorbid functioning). |
Baseline severity | High baseline severity tends to suppress placebo responsivity; it also provides the opportunity for greater variability in severity levels over time than that which occurs with the more restricted range of low baseline severity. |
Chronicity | Long-standing illness states often respond less well than acute episodes to standard pharmacotherapies and incur higher risk for maladaptation to illness over time (e.g., demoralization, diminished effort, loss of social and economic supports). |
Episode number | Patients who have endured multiple episodes may respond less well to lithium than to divalproex (15) and possibly other broader spectrum psychotropics. |
Predominant polarity | Episodes predominated by mania more than depression are associated with better responses to lithium, divalproex, and most second-generation antipsychotics; depression predominance more than mania is associated with better response to lamotrigine and quetiapine plus lithium or divalproex (16). |
Sex | Direct effects of sex on treatment outcome have not been described in bipolar pharmacotherapy trials, although indirect effects may bear on longitudinal outcome (e.g., contraindication of divalproex and pregnancy, elevated postpartum risk for mood episodes, and an artifact of higher prevalence of rapid cycling among bipolar women than men [17]). Sex also may interact with mediating factors (e.g., poorer adherence by men [18]). |
Rapid cycling | Historically defined as the most robust predictor of lithium prophylaxis failure (19), rapid cycling has been recognized as a negative predictor of outcomes during antidepressant trials for bipolar depression (20), a likely indication for the need for combinations of mood stabilizers (21) and a poorer prognostic factor in general (22). |
Psychiatric comorbid conditions | Common psychiatric comorbid conditions in bipolar disorder include anxiety disorders (∼56% (23)), personality disorders (∼65% [23]), OCD (∼17% [24]), adult ADHD (∼10% [25]), eating disorders (∼27% [26]), and posttraumatic stress disorder (4%–40% [27]); few studies have formally examined treatment outcomes of comorbid disorders specifically in patients with bipolar disorder, but any psychiatric comorbidity in general worsens prognosis. |
Alcohol and substance misuse comorbid conditions | Lifetime prevalence of 40%–60% (23) is associated with poorer treatment adherence, higher rates of suicidal behavior, and poorer outcome. |
Medical comorbid conditions | Medical comorbidity burden diminished recovery from depression (OR=0.89) in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) (28); overweight and obesity may directly adversely affect treatment outcome in bipolar depression (29). |
History of childhood trauma | Physical, sexual, verbal, or emotional abuse or neglect during childhood correlates with psychiatric comorbid conditions and vulnerability to psychosis but also stands as an independent negative predictor of treatment outcome in bipolar disorder (30). |
Familiality of drug response | Clinicians often presume that psychotropic drug response is a familial trait, yet there has been remarkably little study of this hypothesis. Concordance of lithium response or nonresponse stands as one of the very few evidence-based examples that drug response by a first-degree relative may inform the likelihood of response in a proband (31). |
Poor or ultrarapid metabolizer genotypes | Less than 10% of most ethnic groups are genetically prone to metabolize substrates of cytochrome P450 2D6, 3A4, or 2C19 either too slowly (“poor metabolizer”) or too rapidly (“ultrarapid metabolizer”), predisposing such individuals to adverse effects or to diminished efficacy or problems hepatically converting some prodrugs to active metabolites, respectively. |
Mediator | Relevance |
---|---|
Treatment adherence | Likely the most obvious and common factor that can adversely affect response to an otherwise efficacious treatment. Prevalence estimates of poor medication adherence in bipolar disorder range from 20% to 60% (18). Poor adherence itself correlates with several moderators of outcome (e.g., illness severity, episode number, and substance use comorbidity [18]), underscoring the complex interplay of treatment moderators and mediators. Nonadherence substantially disrupts judging adequate trials because of inadequate dose or duration. |
Drug-drug interactions | The addition of other pharmacotherapies that alter the bioavailability or metabolism of (or pose pharmacodynamic interactions with) an existing psychotropic drug can obviously alter treatment outcomes. Mental health prescribers are not always aware of changes to pertinent nonpsychotropic drug regimens in this regard, such as hepatic enzyme inducers that can hasten substrate metabolism (e.g., oral contraceptives, omeprazole, phenytoin, and rifampin) or inhibitors that may prolong it (e.g., cimetidine, amiodarone, erythromycin, ketoconazole, allopurinol, nifedipine, quinidine, and ritonavir). |
Therapeutic alliance | The working relationship between prescriber and patient is often underappreciated for its mediating effect on pharmacotherapy outcome partly through its indirect impact on fostering drug adherence but also through its more proximal shaping of attitudes and expectations about likely and realistic expectations of what pharmacotherapy can and cannot do. |
Stressful life events after treatment has begun (e.g., job loss, deaths, pregnancies) | On the one hand, reversals of fortune and interpersonal or other psychosocial stresses (including social rhythm disruptions that may seem benign or beneficial, such as vacations or job promotions) can pose direct triggers for affective relapse (9); on the other hand, optimal treatment should help to foster a sense of resilience in managing unpredictable events or maintaining a sense of emotional equilibrium even in the face of environmental adversity. |
Adverse drug effects or nocebo effects | Drug side effects are proximal contributors to adherence and in themselves can influence perceptions of treatment effectiveness (e.g., adverse effects such as somnolence or akathisia can be mistaken for primary undertreated symptoms, and vice versa; or, even if burdensome side effects do not impede adherence, they may diminish overall well-being and patients’ global perceptions of improvement. |
Substance misuse | Alcohol and illicit substance misuse after treatment initiation can diminish the effectiveness of any pharmacotherapy and exacerbate or perpetuate affective and other symptoms that are themselves the intended targets of treatment. |
Lithium: Gold Standard or Old Standard?
Anticonvulsants: No Mood-Stabilizing Class Effect
Agent | Mania | Depression | Anxiety | Binge eating | Alcohol dependence | PTSD |
---|---|---|---|---|---|---|
Carbamazepine | √ | 1 (+), 2 (−) placebo-controlled trials (48) | 1 (−) placebo-controlled trial in panic disorder (48) | No data | 1 (+) placebo-controlled trial (49) | Case reports, small open trials |
Divalproex | √ | 3 small (+) placebo-controlled trials (48) | 2 (+) placebo-controlled trials (48)b | No data | 1 (+) placebo-controlled trial (50) | 2 (−) placebo-controlled trials (51, 52) |
Lamotrigine | 2 (−) trials (53) | 4 negative acute monotherapy trials (54), 2 (+) augmentation trials (55, 56), and 2 (+) relapse prevention trials (57)c | No data | 1 (−) placebo-controlled trial (58) | No data | 1 (+) placebo-controlled trial (59) |
Gabapentin | 2 (−) trials (53) | 1 (−) placebo-controlled trial (53) | √ | No data | 2 (+) (60, 61) and 1 (−) placebo-controlled trials (62) | Case reports |
Pregabalin | No data | No data | √ | No data | Small open trials | 1 (+) placebo-controlled trial (63) |
Topiramate | 4 (−) trials (53) | No data | No data | √ | 2 (+) placebo-controlled trials (64, 65) | 1 (+) (66) and 2 (−) placebo-controlled trials (67, 68) |
Oxcarbazepine | 1 (−) trial (youth only) (69) | No data | Case reports | No data | Case reports | Case reports |
Zonisamide | 1 (−) placebo-controlled trial (70) | 1 (−) placebo-controlled trial (71) | No data | 1 (+) placebo-controlled trial (72) | 1 (+) placebo-controlled trial (73) | No data |
Second-Generation Antipsychotics
Agent | Acute mania | Mania prevention | Acute depression | Depression prevention | Anxiety | PTSD |
---|---|---|---|---|---|---|
Aripiprazole | √ | √ | 2 (−) placebo-controlled trials (78) | 2 (−) placebo-controlled trials (79, 80)b | Small open trials | 1 (−) small placebo-controlled trial (81) |
Asenapine | √ | √ | No data | √ | No data | Small open trials |
Brexpiprazole | No data | No data | No data | No data | Efficacy in MDD trials with or without anxious distress (82) | No data |
Cariprazine | √ | No data | √ | No data | No data | No data |
Lurasidone | No datac | No data | √ | No data | √ | No data |
Olanzapine | √ | √ | 2 (+) placebo-controlled trials (83) | √ | √ | 1 small (+) placebo-controlled trial (84) |
Quetiapine | √ | √ | √ | √ | √ | 1 (+) placebo-controlled trial (85) |
Risperidone | √ | √d | No data | 1 (−) placebo-controlled trial (86)b,d | 1 (−) placebo-controlled trial for anxiety symptoms in bipolar patients with comorbid panic or GAD (87) | 1 (+) (88), 4 (−) placebo-controlled trials as adjuncts to SSRIs in (nonbipolar) military (89–91) or civilian (92) PTSD |
Ziprasidone | √ | √c | 2 (−) placebo-controlled trials (93) | 1 (−) placebo-controlled trial (94)b,e | 1 (−) placebo-controlled trial in bipolar disorder with comorbid panic disorder or GAD (95) | 2 (−) placebo- controlled trials (96, 97) |
Known Combination Therapy Regimens
Regimen | Illness state | Outcome |
---|---|---|
Lithium + lamotrigine versus lithium + placebo over 8 weeks | Acute bipolar depression | Combination>lithium monotherapy (55) |
Quetiapine + lamotrigine versus quetiapine + placebo over 12 weeks | Acute bipolar depression | Combinationa>quetiapine + placebo (56) |
Lithium or divalproex + lurasidone versus lithium + placebo over 6 weeks | Acute bipolar depression | Combination>lithium or divalproex monotherapy (103) |
Mood stabilizer or antipsychotic + lisdexamfetamine versus mood stabilizer or antipsychotic alone over 8 weeks | Acute bipolar depression | Combination>mood stabilizer or antipsychotic alone (104) |
Divalproex + celecoxib versus divalproex + placebo over 6 weeks | Acute bipolar mania | Combination>divalproex monotherapy (105) |
Treatment as usual + divalproex versus Treatment as usual + placebo over 24 weeks | Bipolar disorder with active alcohol abuse or dependence | Combination>treatment as usual (50) |
Treatment as usual + memantine versus Treatment as usual + placebo over 16 weeks | Bipolar disorder with OCD | Combination> treatment as usual (106) |
Treatment as usual + withania somnifera versus Treatment as usual + placebo over 8 weeks | Cognitive dysfunction in bipolar disorder | Combination> treatment as usual (107) |
Treatment as usual + lurasidone versus Treatment as usual (randomized open label) over 6 weeks | Cognitive dysfunction in bipolar disorder | Combination> treatment as usual (74) |
Lithium + divalproex versus either monotherapy over 20 months | Rapid cycling | Combination>either monotherapy (21) |
Lithium + divalproex versus either monotherapy over 24 months | Bipolar relapse prevention | Combination>divalproex monotherapy (108) |
Using Antidepressants in Treating Bipolar Disorder: When, Not If
Characteristic | More favorable | Less favorable |
---|---|---|
Bipolar II (vs. I) disorder | √ (113) | |
Mixed features | √ (114, 115) | |
Rapid cycling | √ (20) | |
History of treatment-emergent mania or hypomania during prior antidepressant therapy | √ (116) | |
Depression or euthymia (but not mania or hypomania) preceding an index-depressive episode) | √ (117) | |
Robust initial response before continuing longer term antidepressant use | √ (118) | |
History of comorbid alcohol or substance use disorder | √ (119, 120) | |
SLC6A4 “s” allele on pharmacogenetics testing | √ (121) |
Adverse Effects Influencing Medication Choice
Two Case Examples
Case 1
Case 2
Future Directions
Conclusions
Footnote
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