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Vol. 22, No. 04 / November 2010
Associate Professor of Psychiatry and Behavioral Sciences, Department of Psychiatry, Albert Einstein College of Medicine, Bronx, New York, Medical Director, Recognition and Prevention (RAP) Program Director, Adverse Events Assessment and Prevention Unit, Advanced Center for Intervention and Services Research, The Zucker Hillside Hospital, Center for Translational Psychiatry, Glen Oaks, New York, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York
General Treatment Considerations
The principal goals of bipolar disorder (BD) treatment are symptomatic remission (prolonged euthymia) and functional recovery.1 Attaining them requires acute treatment followed by long-term maintenance. Symptom resolution to a level that does not fulfill criteria for the diagnosis of mania or bipolar depression should be regarded as partial success only. Guidelines for patient assessment and evidence-based treatment may provide direction to the clinician, but individualized care requires careful consideration of patient and disease-related variables.2,3 For example, when formulating a treatment plan for an individual patient, different treatment phases and their associated goals should be clearly defined (Figure 1).4 From the outset, the clinician should determine the level of support the patient will need and whether or not hospitalization will be required.
In general, the selection and sequence of medications is dictated by the following considerations: the patient’s symptoms, illness phase and polarity, comorbidities, preferences, previous treatment response, and tolerability; the medication’s efficacy and safety profile and the availability of different formulations/regimens; the clinician’s familiarity with the available medications; and cost considerations. While a relatively large number of medications are approved for the treatment of an acute manic or mixed episode, the only currently approved medications to treat bipolar depression are quetiapine and an olanzapine-fluoxetine combination.5,6 Medications approved for maintenance therapy are also limited. Combination treatment is not uncommon because one agent is often insufficient to address all aspects of the psychopathology and related morbidity.3,7
Treatment is predicated on longitudinal monitoring for symptom and illness response, for medication side effects, and, in the important maintenance phase, for emerging signs of relapse. When a patient relapses, it is important to rule out partial or full nonadherence as the cause before changing the medication. In addition, unusual life events—including a change in living situation, divorce, rape, or some other traumatic incident—can precipitate relapse and should be considered and addressed. In such cases, helping the patient achieve a more stable environment and/or receive targeted psychosocial interventions is likely to be more successful than changing medication(s). Additional causal factors for relapse should be evaluated. Comorbid psychiatric and medical conditions, for example, may complicate and adversely affect the presentation, course, and response to treatment.8-11 Complications such as substance abuse or comorbid anxiety disorder may also contribute to relapse and should be addressed in addition to maintenance therapy for the mood disorder.
Measuring Treatment Effectiveness Over Time
To maximize treatment outcomes and individualize treatment decisions, it is critical to obtain a clear picture of the patient’s symptoms, illness, comorbidities, and past as well as present therapeutic and side effect response. This is best achieved by utilizing evidence- and measurement-based clinical practice tools. Using simple rating scales for assessing depressive and manic symptoms (Table 1)12-19 in clinical practice can help to identify treatment targets and needs in a systematic and scalable way. Time constraints may influence the selection of screening strategies and instruments. Clinicians may use, for example, a 10-point numeric scale indicating patient-perceived and/or clinician-assessed severity of symptoms. The scale may be administered verbally or as a visual-analog scale. Patients can use these scales to rate their symptoms of depression and mania (scale of 0–10, with 0 being normal). Another approach, the Clinical Global Impression (CGI) severity and improvement scale (severity scale of 1–7), has been widely used in both clinical trials and in clinical practice.20
Number of items included in the questionnaire
What is measured
Method for completion
Approximate time required
Measurement of depressive symptoms
Core symptoms of depression
Completed by clinician, based on patient interview and evaluation
21 or 17 items
The 17 items measure symptoms of depression. In addition, 4 items assess factors such as diurnal variation of depressive symptoms and the presence of additional features (ie, depersonalization, paranoid symptoms, and obsessional symptoms).
0-4 or 0-2
Completed by clinician, based on patient interview and evaluation
IDS30 : 30 items QIDS16 items Uses DSM-IV criteria for major depressive disorder
Additional items assess melancholic and atypical symptom features.
0-3, measures severity and frequency of specific symptoms over last 7 days
Both IDS30 and QIDS16 are available in the patient- and clinician-rated versions
IDS-C30 : 10-15 minutes QIDS-C16 : 5-7 minutes 15,16 (IDS-C30 and QIDS-C16 represent the clinician-rated version)
Uses 9 DSM-IV criteria
0-27 for total scores from the 9 criteria, 0-3 of daily frequency
Reported by patient, scored by clinician
<2 minutes for clinician scoring15
Measurement of mania
Core symptoms of manic phase, addresses full range of possible severity. For each item, severity ratings are based on the patient’s report during the past 48 hours and the clinician’s observations during the interview.
0-4 for 7 items, 0-8 for 4 items
Completed by clinician
HAM-D: Hamilton Rating Scale for Depression; IDS30: Inventory of Depressive Symptomology (30-item);
MADRS: Montgomery-Asberg Depression Rating Scale; PHQ-9: Patient Health Questionnaire; QIDS16: Quick Inventory of Depressive Symptomology (30-item); YMRS: Young Mania Rating Scale.
Life-chart methodology is a validated technique that provides continuous daily measurements of symptom fluctuations.23 A version of a mood chart can be obtained freely from the internet.24 Patient involvement in the life-chart enhances the therapeutic relationship, fosters treatment adherence, helps to destigmatize bipolar disorder, and enables patients to be active and informed participants in their disease management.25 Further, this method allows documentation and anticipation of treatment resistance, cycle acceleration, discontinuation-induced treatment refractoriness, and possible switches in polarity.
Validated tools are available to evaluate symptom remission—that is, sustained euthymia. Although remission of mania is generally defined as a score of less than 12 on the Young Mania Rating Scale (YMRS), recent reports suggest the qualifying YMRS score should be lowered to no more than 8.26,27 Patients should also present without relevant levels of depression, for example, characterized by a score of no more than 10 on the Montgomery-Asberg Depression Rating Scale (MADRS), although cut off scores of ≤12 and ≤5 (for complete remission) have been reported as well.28-30 Functional recovery requires significant progress across educational, vocational, and psychosocial domains. In this context, management of residual symptoms is critical to the achievement of long-term goals. Residual symptoms are present if, after treatment, the patient retains a mild to moderate depression, mania, or psychosis. Data from one prospective cohort study suggest that residual threshold or subthreshold symptoms of mood elevation predispose patients to relapse into mania and depression.1 Similar results were observed in a 2- to 4-year follow-up study of patients who were hospitalized for first manic/mixed episodes. Predictors of recurrent mania included initial psychosis and initial manic presentation, whereas initial mixed presentation and comorbidity were associated with recurrent depression.31 Further, functional recovery is most likely when medication treatment is combined with psychosocial management approaches.32
Current guidelines address several dimensions of evidence for medication efficacy, which usually constitutes 2 positive placebo-controlled trials (level A evidence).22 However, since numerous medications are available that fulfill these criteria, recent guidelines incorporate differences in side effect profiles or other issues that may potentially interfere with overall effectiveness into the level of recommendation.33,34 During acute treatment, side effects that can cause therapy discontinuation (eg, marked extrapyramidal symptoms [EPS] or akathisia, dystonic reaction, fainting/syncope, marked sedation, or severe gastrointestinal [GI] side effects) should be avoided and the long-term consequences of treatment thoroughly assessed. Longer-term side effects can include endocrine problems such as thyroid dysfunction, polycystic ovary syndrome like symptoms (PCOS) and prolactin abnormalities, metabolic complications (eg, dyslipidemia, diabetes), weight gain, sexual dysfunction, and tardive dyskinesia (TD).
Patients on antidepressants may experience nonspecific symptoms such as agitation, anxiety, insomnia, GI disorders, or sexual dysfunction.35 In addition, in adolescents and young adults, suicidal behaviors can possibly emerge, prompting an FDA warning. Importantly, these agents can sometimes precipitate mania and induce or accelerate rapid cycling.36 A recent meta-analysis, for example, showed that adding an antidepressant to a mood stabilizer reduced overall risk of depression recurrence by approximately 27%, but also conferred a 72% increase in the risk of new episodes of mania (including hypomania and mixed states).36 An antidepressant-induced mood switch into hypomania or mania is an increasingly well-characterized phenomenon. For instance, in a double-blind study in which patients were evaluated after 8 weeks of acute treatment and during maintenance treatment for up to 1 year, bupropion was less likely to induce mood elevation (1 of every 9 patients) than desipramine (5 of every 10 patients).37 In other studies, risk of switches into hypomania or mania was significantly higher in patients treated with venlafaxine compared with bupropion, or sertraline, or paroxetine.38,39
Risk factors for antidepressant-induced mania include BD I, a history of antidepressant-induced mania or hypomania, a manic phase preceding the current depressive episode, and mild or subthreshold mania symptoms during a depressive episode.40-45 Alcohol or substance abuse, use of tricyclic antidepressants (TCAs) or serotonin and norepinephrine reuptake inhibitors (SNRIs), and hyperthymic traits also appear to increase this risk.46-48 While these data suggest an unfavorable risk/benefit profile for long-term antidepressant therapy in BD, especially BD I, some patients with resistant depression or others receiving concomitant mood stabilizing agents, especially those with BD II, may benefit from adjunctive antidepressant therapy.36 Further studies are needed to guide individual-ized treatment approaches for these patient subpopulations and decisions need to be made on a case-by-case basis.35Table 2 provides select data for assessing antidepressant candidacy.35,40,42,43,45,49-53
Favors antidepressant use
Discourages antidepressant use
Bipolar II disorder
Bipolar I disorder40
Depressed (nonmixed) states
Absence of rapid cycling
Absence of recent mania or hypomania (preceding 2 to 3 months)
Mania or hypomania in past 2 to 3 months43
Absence of comorbid alcohol or substance use disorder
Prior favorable antidepressant response
Suboptimal responses to prior antidepressants
No history of antidepressant-induced mania or hypomania
History of antidepressant-induced mania or hypomania45
Although side effects remain a concern with all mood stabilizers and anti-psychotics, the focus has shifted in recent years from awareness of GI and neuromotor side effects to suicidality and cardiovascular and metabolic risk factors, such as coronary artery disease, hyperlipidemia, weight gain, insulin resistance, and diabetes. Common side effects and Black Box warnings for mood stabilizers and antipsychotics are summarized in Table 3.3,5,6,54-66 Risk factors for suicide should be assessed proactively, not only as a side effect precaution but as part of general management. These risk factors include clinical deterioration, agitation, comorbid personality disorders and substance misuse, mixed episodes, and a personal or family history of suicide.5,6,54,55,57,61,67
Interestingly, patients with BD and schizophrenia, at least when each patient population is treated with second-generation antipsychotics, have similarly elevated rates of metabolic syndrome.68 This suggests that patients with BD and schizophrenia share a susceptibility to antipsychotic-associated metabolic effects, which is unrelated to psychiatric diagnosis or concomitant mood stabilizer therapy.68 At least during antipsychotic monotherapy and in patients who received prior antipsychotic treatment, olanzapine and clozapine have been associated with the largest weight gain, risperidone and quetiapine appear to be associated with intermediate weight gain, and aripiprazole and ziprasidone have the least weight gain potential.69-71 Some evidence suggests that both first-episode and antipsychotic-naïve patients are at highest risk for antipsychotic-induced weight gain and metabolic side effects, and that none of the antipsychotics is fully weight neutral.72-75 Although risperidone and quetiapine seem to have a similar weight gain potential, quetiapine appears to be associated with a greater liability to cause metabolic abnormalities, especially dyslipidemia.72,73 The only head-to-head comparison study of aripiprazole and ziprasidone showed no difference in weight gain and metabolic risk potential between the two medications.76
Assessing the risk for cardiometabolic side effects involves weight gain measurement at each clinical visit plus encouragement of patient self-monitoring, as well as assessment of blood pressure, fasting blood glucose, and lipids.69 Further discussion follows.
Although EPS and TD are generally of less concern with second- generation antipsychotics than with older agents, clinicians should assess motor function at baseline and monitor motor side effects during titration of the antipsychotic dose and at 3-month intervals once the target dose has been reached. The Simpson-Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS) should ideally be administered at baseline (or during titration for the SAS) and every 3 months thereafter to monitor for EPS and TD.20,77,78 When it is not possible to complete a full SAS, moving the patient’s elbow or shoulder to test for stiffness/resistance and observing the patient’s gait can provide a useful general assessment of EPS. Similarly, when it is not possible to perform a full AIMS, observing the patient’s face and tongue with the mouth open allows the clinician to detect the most frequently occurring orofacial movement abnormalities. The Barnes Akathisia Scale, which involves assessment of movement as well as awareness of restlessness and global clinical assessment of akathisia, is also recommended for monitoring akathisia at baseline during dose titration and 3 months thereafter.79
As with the antipsychotics, the side effect profiles of mood stabilizing agents warrant ongoing monitoring. Several studies have demonstrated endocrine-related side effects for mood stabilizing agents. Lithium may induce hypothyroidism, while females of childbearing age treated with valproate may present with PCOS.80-82 Reproductive system features of PCOS include amenorrhea or oligomenorrhea and hyperandrogenism, which may cause acne, hirsutism, and male pattern balding.83 Blood tests should be obtained during titration and maintenance treatment to rule out these and other side effects (further discussion below).
Common side effects
Black Box warnings
Special monitoring recommendations
Signs and symptoms of hepatic, hematologic, or dermatologic side effects; CBC and platelet measurements during the first 2 months, liver function tests every 2 weeks; thereafter, blood counts and liver function tests at least every 3 months, with more frequent monitoring in patients with signs of hematologic or hepatic abnormalities3
Gastrointestinal symptoms (nausea, vomiting, heartburn); less frequently, dermatologic effects (rash, alopecia), neurologic effects (drowsiness, irritability, ataxia), low platelet count, and hair loss59
Hepatotoxicity, teratogenicity, pancreatitis61
PCOS may develop with VPA treatment; for stable patients taking VPA, monitor hematologic and hepatic function at least every 6 months; patients who are unable to reliably report signs and symptoms of VPA toxicity should be monitored more frequently3
Dizziness, ataxia, somnolence, headache, double vision, blurred vision, nausea, rash59
Life-threatening serious rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death; additional factors that may increase risk of rash may include coadministration with valproate and exceeding recommended initial dose or dose escalation of lamotrigine57
Instruction to patient and family to report each rash and routine inquiry about this
Before starting lithium, review patients’ general medical history, physical exam report, BUN, creatinine level, pregnancy test, thyroid function. For patients older than 40 years, review ECG with rhythm strip and CBC findings; monitor for neurologic toxicity3,60,62
Nausea, vomiting, light-headedness, somnolence, constipation, postural dizziness, restlessness, akathisia59
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders54
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter54
Somnolence, dizziness, EPS other than akathisia, weight gain58
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs58
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter58
Drowsiness, postural hypotension, EPS63
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs63
Frequent CBC during first few months of treatment for patients with pre-existing low WBC count or a history of drug-induced leukopenia/neutropenia63
Dry mouth, edema, postural hypotension, weight gain, elevated plasma glucose and triglycerides59
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs64
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter64
Disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, blurred vision, weight gain5
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders5
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter5
Dry mouth, sedation, dizziness, somnolence, postural hypotension, weight gain59
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs; increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders6
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Initial lens examination (for cataracts, based on animal data only) when starting treatment and every 6 months thereafter; blood pressure measurement at initiation of, and potentially during treatment in children and adolescents6
EPS at high doses, weight gain, tachycardia, hyperprolactinemia, headache, dizziness, abdominal pain59
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs65
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Orthostatic vital signs in patients for whom orthostatic hypotension is of concern65
Somnolence, EPS including akathisia, dizziness, abnormal vision, asthenia, vomiting66
Increased mortality in elderly patients with dementia-related psychosis who are treated with antipsychotic drugs66
Weight, BMI, and healthy lifestyle routinely; fasting glucose, lipids, and blood pressure at baseline, 3 months, 12 months, and annually; EPS and abnormal involuntary movements at baseline, during titration, and 3-monthly thereafter. Baseline serum potassium and magnesium measurements for patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances; patients with low serum potassium and/ or magnesium should be repleated prior to treatment to avoid ECG/cardiac conduction abnormalities66
BMI = body mass index; BUN = blood urea nitrogen; CBC = complete blood cell;
ECG = electrocardiogram; EPS = extrapyramidal symptoms; MDD = major depressive disorder;
PCOS = polycystic ovary syndrome; VPA = valproic acid; WBC = white blood cell
Any medical issues that may affect treatment and response to treatment should be considered and monitored. Further, when the white blood cell (WBC) count is low or there is a history of drug-induced leukopenia/neutropenia, complete blood cell (CBC) count should be frequently evaluated during the first few months of treatment.5,6,54,58,63-66,84
Current guidelines recommend measuring prolactin levels when signs and symptoms suggest the presence of clinically important hyperprolactinemia (ie, sexual dysfunction with impairment of libido, arousal, orgasm, or performance, or associated problems such as gynecomastia or galactorrhea in males, or amenorrhea, oligomenorrhea, galactorrhea, or breast tenderness in females).2,77 If prolactin levels are elevated, a dose reduction or switch to a prolactin-sparing medication should be considered. Only in cases where these measures do not reduce markedly elevated prolactin levels (>200 ng/dL) or where temporal visual field defects are noted, an MRI of the sella turcica should be performed to rule out a possible secreting prolactinoma.85
Response to antipsychotic therapy varies considerably between patients. While the patient-specific genetic, neurochemical, and psychosocial factors underlying this differential responsiveness to individual agents are not firmly established, evidence-based recommendations support thorough baseline assessment and tight clinical management. Certainly, clinicians should address efficacy, metabolic risk, patient preference, and other factors that can contribute to improved adherence and treatment success.3 Table 4 describes recommendations for monitoring weight, blood pressure, and metabolic parameters in patients receiving second-generation antipsychotics.69 Physical assessment and blood analysis for full blood count, electrolytes, thyroid function, fasting glucose, and lipid profile should be performed at baseline. For patients on mood stabilizers, blood tests should be obtained during titration and maintenance treatment, including thyroid function for lithium and complete blood count for valproate (to rule out thrombocytopenia) and for carbamazepine (to rule out leukopenia). In addition, therapeutic blood levels of lithium, valproate, and carbamazepine should be monitored. Longitudinal examination is critical, providing the basis for therapeutic adjustments, side-effect management, and switching medications, as needed.
Every 5 years
Fasting plasma glucose
Fasting lipid profile
*All subsequent guidelines endorse annual (instead of 5-yearly) lipid monitoring, coinciding with glucose monitoring.
Poor adherence to medications is common in patients with BD.86,87 For example, a large study (N=1500) demonstrated that the mean duration of continuous lithium adherence was as short as 76 days.88 Poor adherence is a multifactorial problem that varies on a patient-by-patient basis, and can be attributed in part to intolerable side effects, breakthrough symptoms, ineffective treatment, stigma of taking medications, a negative attitude towards medications in the close environment, concerns about the long-term side effects of medications, a dislike of having one’s mind or mood altered by medications, complex medication regimens, disorganization or forgetfulness, lack of awareness about the consequences of nonadherence, and practical issues, such as cost.89-92 Patients will normally show worse adherence in some phases of illness than others.91 The manic phase of BD, for example, may be associated with an elevated risk of nonadherence, possibly due to limited insight or cognitive dysfunction.91,93 Concurrent conditions such as substance abuse and cognitive deficits may also adversely affect adherence.92,94 Nonadherence is associated with severe consequences, including lowered response during acute episodes, more relapse rates in general, higher relapse rates during euthymic periods, reduced quality of life, and ultimately, loss of remission, increased hospitalization, and suicide attempts.95
Several methods can be used to track patient adherence (Figure 2).96 Most studies of nonadherence have been confounded by self-report or provider-report methods, which are often indirect and unreliable.96 Objective methods, such as pill counts and electronic refill data, provide a more direct assessment but also have important limitations. For example, an electronic monitoring system using a microchip in the bottle cap indicates when the bottle was opened, but not whether the medication was actually ingested.96 Biological markers of adherence, such as blood and urine levels, can provide a snapshot at the time of measurement and may work best with home visits.96
In their expert consensus meeting, Velligan and coworkers agreed that a medication gap of at least 1 week without medication satisfied the minimal threshold for “nonadherence”.97 The second largest group of clinicians participating in this survey defined 4 consecutive days with no medication intake as nonadherence. Additional data underline the importance of monitoring adherence. First, among patients with schizophrenia, a 1–10-day medication gap doubled the odds for rehospitalization.98 Although similar data are not available for patients with BD, a medication possession ratio (MPR) below 0.75 has been associated with an increased risk of rehospitalization following hospital discharge.99 Clearly, well-designed studies are required to evaluate a working definition of nonadherence, the effects of nonadherence on patient outcomes, and strategies designed to overcome barriers to improved adherence.
Numerous studies and expert opinion support the need for routine monitoring of past and present patient adherence. Insights into patient attitudes towards and problems with their medications—including treatment-related side effects—can help clinicians identify factors that complicate adherence to the prescribed regimen.97 If there is a noticeable worsening in symptoms, nonadherence should always be suspected and ruled out as one of the possible reasons. Patients are not always the best informants, since they may conceal their nonadherence to avoid embarrassment to self or the doctor. In such cases, interviewing family members or significant others about adherence may be useful. If a patient is relatively new to the clinician and has a history of adherence, assessments made monthly or during each visit are recommended.97 If a patient has a history of nonadherence, weekly updates are recommended, particularly when a worsening of symptoms occurs, to avoid relapse and rehospitalization.97
Improving communication with the patient through psychosocial interventions and family involvement can significantly improve adherence. Table 5 lists psychoeducational strategies for patients and their families that can be helpful in achieving this goal.97 Useful Information for a family’s understanding of the disease and potentially helpful interventions for dealing with a patient’s depressive symptoms and mania are listed in Table 6.100
Cognitive behavioral therapy
Interpersonal and social rhythm therapy
Depressed mood, loss of interest or pleasure in nearly all activities, social withdrawal
Inability to concentrate, difflculty in constructing sentences
Decreased energy, tiredness, and fatigue, even without physical exertion Sense of worthlessness or guilt
Reduced appetite and weight loss Changes in sleep patterns, most commonly insomnia
Elevation in affect (mood)
Manic speech, usually loud and difficult to interrupt
Increased physical mobility, energy, and restlessness
Decreased need for sleep, most active at night Expansiveness and recklessness such as extensive conversations with strangers, spending sprees, driving fast
Delusions and hallucinations, especially of a grandiose nature
Pharmacologic strategies to optimize efficacy and minimize side effects include dose adjustment, addition of adjuvant medications, and switching of medications. Nonpharmacologic strategies such as healthy lifestyle counseling and intervention and various forms of psychotherapy may also be helpful and deserve additional study. For generally stable patients on a new therapeutic regimen, it is advisable to wait 2 to 4 weeks to determine if the change(s) resulted in improved efficacy.2 For an acutely ill patient who requires more rapid symptom improvement, it may be prudent to try a different strategy sooner, possibly within 7 to 10 days, although well-designed studies are needed to further research this issue. Patients with medical comorbidies or those who develop treatment-related medical complications such as diabetes, hyerlipidemia, or hypertension may benefit from a specialist consult and, possibly, further management.
To ensure that the patient has achieved maximal treatment efficacy, and if the patient has achieved at least a partial response, the dose should be optimized before another medication is added or a switch is performed. Medications should be titrated to efficacy or to maximum-tolerated dose. If there are no dose-limiting side effects that significantly influence patient function, dose may be titrated upward to the therapeutic limit, as long as a thorough monitoring plan is in place.
The American Psychiatric Association (APA) guidelines recommend combination therapy for patients who have severe mania or who do not respond adequately to monotherapy.2,3 If a patient has dose-limiting side effects and/or an insufficient treatment response, switching medications or adding an adjuvant medication should be considered. Switching medications is preferable, since it avoids the drug-drug interactions, side effects, and adherence-limiting complexity associated with adding medication. However, for patients whose psychiatric stability is either tenuous or very good, switching medications can be destabilizing. In fragile patients and in those who have shown clinically relevant (though perhaps insufficient) improvement on the first agent, it may be more appropriate to add another pharmacologic agent. When adding medication, potentially additive side effects should be monitored and drug-drug interactions should be anticipated and minimized as much as possible.
For patients with acute bipolar mania, numerous studies have demonstrated that combination therapy with an antipsychotic plus a mood stabilizer is superior to mood stabilizer monotherapy.101 For acute treatment of mania/mixed episodes, aripiprazole, asenapine, olanzapine, quetiapine, risperidone, or ziprasidone can be used with lithium or valproate, while long-acting risperidone is currently indicated for maintenance therapy.6,54,64-66,84 (see Table 1 in Chapter 2, Medical Management of BD)
As a general approach to BD management, adding another agent to an existing treatment regimen (augmentation/combination therapy) is often appropriate, particularly when medications with complementary mechanisms of action and target symptoms can be used together. Exceptions to this general rule are notable. For instance, if a patient is not tolerating the current medication, or has gained no benefit at all or, even, showed worsening of symptoms or functioning, then switching is more appropriate. Adding a medication can accelerate a therapeutic response, as has been reported for example when combining an atypical antipsychotic with a conventional mood stabilizer, such as lithium or valproic acid.102,103 Further, if the addition of an antipsychotic to a mood stabilizer is ineffective, then a trial with the same antipsychotic as monotherapy can be avoided. Numerous studies have shown that combination therapy is likely to achieve better response and remission rates and may be associated with increased adherence.96,101 Side effects can be minimized by careful titration, consideration of potential drug-drug interactions, and using sub-maximal doses of each medication. As part of a combination regimen, it is reasonable to continue lithium due to its neuroprotective and anti-suicidal benefits.104
Switching may be considered when a patient has been responsive to other medications in the past. Further, the clinician should consider switching a medication for patients who experience residual symptoms that cause distress or impair functioning—that is, partial, inadequate, or nonresponsiveness—or side effects that are severe or impairing. Switching antipsychotics can be associated with destabilization and is sometimes complicated by potential withdrawal or rebound effects.105 These rebound effects can make it difficult to interpret the efficacy of a new agent, since any insufficient efficacy can be due to either discontinuation-related exacerbations or continuation/exacerbation of illness-related symptoms. Table 7 lists corrective strategies during the initial switch period.105
It is important to utilize switching practices that accommodate differences in pharmacodynamic side effects (Table 8).106 For example, a slower, overlapping switch may be required to avoid rebound side effect phenomena (eg, rebound anxiety, insomnia, or agitation) from histaminergic or cholinergic blockade (Figure 3).105-107 Rebound can also occur if the dose of a new medication is not sufficiently high, as observed when switching from a high-affinity dopamine receptor antagonist (eg, high or medium potency first-generation antipsychotics, paliperidone, risperi-done, iloperidone)—to a lower affinity dopamine receptor antagonist (eg, quetiapine, clozapine) or to a partial dopamine agonist (aripiprazole). Switching to an agent with a strong 5-HT2A blockade relative to a dopamine blockade (eg, ziprasidone, especially when underdosed or not taken with food) can cause a similar effect.105 This can manifest as transient intraswitch restlessness or worsening of psychosis, mania, or agitation, and should be monitored and possibly be treated by increasing the dose of the postswitch antipsychotic or by adding sedating medications until the switch has been completed successfully.105
Differences in half-life or absorption can result in pharmacokinetic rebound phenomena, for example, when the switch is abrupt, from a drug with a shorter half-life to a drug with a longer half-life.105,106 Half-lifes for second-generation antipsychotics and selected first-generation antipsychotics are shown in Table 9.58,107 When worsening symptoms necessitate an expedited switch or when a rebound phenomena complicates a switch, coprescription of a benzodiazepine, valproic acid, or antihistamine may reduce these symptoms and facilitate the process.105
As reviewed in Chapter 2, Medical Management of BD, including steps for the switch process, changing from an oral to a long-acting injectable antipsychotic can be an effective option for patients, particularly for those who are nonadherent to oral antipsychotic therapy.108
Corrective approach or (transient) adjuvant medications
Antipsychotic, antimanic, antiaggressive, EPS/akathisia, tardive dyskinesia, increased prolactin
Psychosis, mania, agitation, akathisia, withdrawal, dyskinesia
Anxiolytic, sedation, weight gain, anti-EPS/akathisia
Anxiety, agitation, insomnia, EPS/akathisia
Memory, cognition, dry mouth, anti-EPS/akathisia
Agitation, confusion, psychosis, anxiety, insomnia, sialorrhea, EPS/akathisia
Blurry vision, constipation, urinary retention, tachycardia, hypertension
Diarrhea, diaphoresis, nausea, vomiting, bradycardia, hypotension, syncope
Both conventional and second-generation antipsychotics are associated with side effects that differ in type and/or degree. Sedation is a common side effect for low-potency conventional agents, especially, when taken in high doses, whereas it is less frequent with high-potency conventional agents and second-generation agents, except for clozapine, quetiapine, and, possibly, olanzapine. The sedative effects of quetiapine and clozapine are attributed to its very strong binding to sedating histamine H1 receptors, starting at very low doses.109 Patients with bipolar disorder may require interventions to manage endocrine or cardiometabolic issues, such as weight gain and obesity, hyperlipidemia, hyperglycemia, and arterial hypertension. Table 7 lists strategies that can be used to acutely manage the undesirable side effects of antipsychotics, particularly those likely to occur early in treatment.105 For example, evidence suggests that adding a dopamine agonist or partial agonist such as aripiprazole reduces prolactin levels and alleviates related symptoms in patients with risperidone- or haloperidol-induced hyperprolactinemia.110,111 Likewise, metformin or topiramate may benefit patients with antipsychotic-induced weight gain.112 Patients who develop diabetes, clinically relevant dyslipidemia, or hypertension should be referred to a primary care practitioner or an endocrinologist.
Serious mental illness is associated with a lifespan that is shortened by 20 to 30 years.113 A 2006 study of the persistently mentally ill showed a significantly elevated rate of premature mortality mainly due to cardiovascular disorders.113 Other mortality studies have produced similar results.114 The higher rate of mortality in patients with BD is likely due to a higher prevalence of dyslipidemia, metabolic syndrome, obesity, diabetes, hypertension, and smoking than in the general population.115 Patients with both BD and metabolic syndrome often present with complex conditions, the course, outcome, and treatment responsiveness of which are far more serious when compared to age-matched controls.116 These comorbidities also adversely affect health-related quality of life across time.117 Importantly, implementation of a BD medical-care model, a manual-based psychoeducational intervention that incorporates content on cardiovascular disease-related risk factors, has demonstrated significant health benefits in this vulnerable patient population.118 Selecting appropriate medications to achieve symptomatic control in patients with BD is critically important for therapeutic success. Equally important is the role of long-term monitoring, particularly of cardiometabolic risk factors, suicidality, and nonadherence, owing to, among several common reasons, negative attitudes towards medications and/or problematic treatment-related side effects, Based on these findings, clinicians can tailor psychoeducation strategies accordingly, emphasizing healthy lifestyle behaviors, improved diet and exercise, and the importance of the mutually reinforcing relationship between improved somatic and mental health.
Bipolar disorder is a severe and often chronic disorder associated with significant functional impairment, increased disability, and a high incidence of relapse. Careful monitoring, the use of measurement tools and scales, and adequate management of available treatments can enhance the effectiveness of overall disease management. Residual symptoms, comorbidities, side effects, and nonadherence may interfere with treatment success. Measurement-based evaluation and monitoring of treatment efficacy and side effects via multimodal individualized treatment has the greatest chance of maximizing treatment outcomes in patients with BD.
Functional and subjective domains such as subjective well-being, quality of life, and functional capacity are important in this patient population. Adverse drug reactions, along with weight gain and obesity, may impair mental well-being, quality of life, and medication adherence.98 Weight gain and obesity are also closely related to life-shortening medical comorbidities.98,113
Treatment guidelines are useful for clinicians seeking a sequenced treatment approach that takes into account level A evidence from at least 2 randomized, controlled positive trials for a given medication. Treatment guidelines also help the clinician select treatments with the best efficacy/ safety balance tailored in a shared decision-making process to the individual patient and illness phase. A personalized treatment approach may improve the psychiatric prognosis, while enhancing treatment alliance and the adherence status of the patient. A holistic psychosocial approach that considers the physical and mental health, as well as the social, educational and vocational functioning of the patient with BD is essential for optimizing treatment outcomes.
Annals of Clinical Psychiatry ©2010 Quadrant HealthCom Inc.