Geriatric Bipolar Disorder - Acute Treatment PDF

Geriatric bipolar disorder: Acute treatment
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Geriatric bipolar disorder: Acute treatment Authors Martha Sajatovic, MD Peijun Chen, MD, MPH, PhD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Jan 31, 2013. INTRODUCTION The clinical features and treatment of older bipolar patients differ from those of younger patients [1]. Up to 25 percent of all bipolar patients are elderly [2], and the absolute number of geriatric bipolar patients is expected to increase as the worlds population ages over the next several decades [3,4]. This topic reviews the acute treatment of geriatric bipolar disorder. The epidemiology, pathogenesis, clinical features, assessment, diagnosis, maintenance treatment, and prognosis of geriatric bipolar disorder are discussed separately, as are the clinical features, diagnosis, acute treatment, and maintenance treatment of bipolar disorder in mixed-age patients. (See "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis".) (See "Geriatric bipolar disorder: Maintenance treatment and prognosis".) (See "Bipolar disorder in adults: Epidemiology and pathogenesis".) (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) (See "Bipolar disorder in adults: Pharmacotherapy for acute depression".) (See "Bipolar disorder in adults: Maintenance treatment".) DEFINITION The minimum age used to define geriatric bipolar disorder is generally 60 years [5]. However, some authorities use an age cut-off of 50, 55, or 65 years [6]. Geriatric bipolar disorder includes both aging patients whose mood disorder presented earlier in life, and patients whose mood disorder presents for the first time in later life [1,7]. Bipolar disorder is characterized by episodes of major depression (table 1), mania (table 2), and hypomania (table 3), as well as mixed episodes (major depression concurrent with mania) [8]. However, the clinical features of bipolar disorder are different for older and younger patients in that [1,9-12]: Cognitive impairment is more common and severe in geriatric patients Comorbid general medical illnesses are more common in older patients Excessive sexual interest and behavior during manic or hypomanic episodes appear to be less common in older patients Comorbid anxiety and substance use disorders may be less common in geriatric patients The clinical features and diagnosis of geriatric bipolar disorder are discussed separately. (See "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis", section on 'Clinical features' and "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis", section on 'Diagnosis'.) TREATMENT Goal The goal of acute treatment for late-life bipolar mood episodes is remission, which is defined as resolution of the mood symptoms or improvement to the point that only one or two symptoms of mild intensity persist. If psychotic features (delusions or hallucinations) are also present, resolution of the psychosis is required for remission. For patients who do not achieve remission, a reasonable goal is response, which is defined as stabilization of the patients safety and substantial improvement in the number, intensity, and frequency of psychotic and mood symptoms. Response can be quantified with standardized rating scales such as the Brief Psychiatric Section Editors Paul Keck, MD Kenneth E Schmader, MD Deputy Editor David Solomon, MD
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Rating Scale (assesses psychosis) [13], Young Mania Rating Scale (assesses mania) [14], and the Patient Health Questionnaire Nine Item (assesses depression) (table 4) [15], but this is not standard clinical practice. General principles Treatment for geriatric bipolar patients begins with a psychiatric and general medical history, mental status and physical examination, and focused laboratory and imaging studies. The evaluation establishes the mood symptoms and comorbid disorders that require treatment, as well as any contraindications to treatment (eg, renal impairment and use of lithium, or hepatic disease and use of valproate). The assessment for late-life bipolar disorder is discussed separately. (See "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis", section on 'Assessment'.) The treatment setting for geriatric bipolar disorder depends upon the type and severity of symptoms, comorbid psychopathology (eg, substance use disorder), level of psychosocial functioning, and available support. Hospitalization may be required for safety and stabilization, particularly for severely ill patients with: Suicidal ideation with a specific plan and intent Delusions or hallucinations that place the patient at imminent risk of coming to harm Substance dependence that is exacerbating the mood episode Impaired functioning (eg, inability to feed or clothe oneself) Moderately ill patients with late-life bipolar disorder can be treated in a partial hospital (day) program or residential facility (eg, nursing home), including patients with suicidality that does not pose an imminent risk (eg, fleeting thoughts of killing oneself with vague or nonexistent plans and no intent). An outpatient clinic may be suitable for less acutely ill patients (eg, thoughts that family members would be better off if the patient was dead, with no plan or intent to commit suicide). Evidence for the efficacy of medications includes subgroup analyses of results for geriatric patients enrolled in randomized trials conducted with mixed-age adult bipolar patients (18 to 65 years). These studies generally show that response is comparable for older and younger patients [16,17]. Other evidence consists of open-label prospective studies, retrospective studies, and case reports. Treatment of geriatric mania, bipolar major depression, and mixed episodes may require a combination of two psychotropic medications [18,19]. In addition, mood episodes with psychotic symptoms generally require treatment with a second-generation antipsychotic such as quetiapine or olanzapine, either as monotherapy or combined with lithium or valproate [20]. Geriatric bipolar mood episodes secondary to a general medical condition are managed with concurrent treatment of the medical condition and mood symptoms. Mood episodes due to general medical conditions are discussed separately. (See "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis", section on 'General medical conditions'.) Compared to younger patients, geriatric bipolar patients often require more vigilant monitoring of therapeutic and adverse medication effects [21]. Hospitalized geriatric patients are monitored daily. Outpatients are commonly seen on a weekly basis until they have responded (ie, the number, intensity, and frequency of mood symptoms has improved by at least 50 percent) and have tolerated the medication regimen for two to four weeks. At that point the patient can be seen every two to four weeks until they remit. Patients who suffer a recurrence of mood (or psychotic) symptoms or develop new side effects may need to resume a more frequent schedule of visits, depending upon the severity of symptoms. Patients with geriatric bipolar depression may possibly benefit from adding group psychoeducation to pharmacotherapy. An open-label study evaluated a 12-week, adjunctive group psychoeducation program focused upon medication adherence in 21 older bipolar patients, most of whom were depressed [22]. Clinically small to moderate improvement in depressive symptoms occurred in the 16 patients who completed the study. Pharmacologic issues Clinicians should start low and go slow when prescribing medications for geriatric bipolar patients, especially frail, medically compromised patients who have difficulty tolerating medications [23-25]. Comorbid diseases, concomitant medications, and age-related physiologic changes can alter a drugs pharmacodynamics and pharmacokinetics, which often affect therapeutic and adverse responses. Thus, pharmacotherapy generally requires:
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Starting the drug at a low dose Increasing the dose by small increments every one to seven days Caution regarding side effects Older bipolar patients taking multiple medications due to comorbid illnesses are at risk for drug-drug interactions. Specific interactions of any particular drug with other medications may be determined by using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions. Manic, hypomanic, and mixed episodes Pharmacotherapy is generally used for geriatric manic, hypomanic, and mixed episodes. Despite clinical differences among these types of mood episodes, for the purpose of treatment they are considered to be similar and thus treated with the same medications [23,26,27]. For refractory mania or mixed episodes, electroconvulsive therapy (ECT) can be beneficial. First line medications First-line medications for geriatric mania, hypomania, and mixed episodes include quetiapine, olanzapine, lithium, and valproate, based upon randomized trials in mixed-age adults [28-31] and other studies in older patients [1,18,19,21]. No head-to-head trials have compared these drugs in the elderly. The specific choice is thus based upon other factors, including past response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. Clinicians can generally expect that approximately 50 to 60 percent of patients will respond to a first-line treatment, based upon study results [16,21,32]. Quetiapine In elderly bipolar patients, quetiapine is usually started at 12.5 to 25 mg once daily or 25 to 50 mg per day in two divided doses [18,33]. The dose is then increased every two to five days by increments equal to the starting dose to reach the target dose of 100 to 300 mg per day, taken in two divided doses. For patients who neither respond to 300 mg per day nor are troubled by side effects, the dose may be increased up to 800 mg per day [16]. However, many patients will not tolerate higher doses due to sedation and orthostasis. Common side effects observed in older manic patients treated with quetiapine include dry mouth, sedation, postural hypotension and dizziness, dyslipidemia, hyperglycemia, and weight gain [1,16]. Fall risk may be increased in elderly people with sedation and postural hypotension. In addition, second-generation antipsychotics are associated with an increased risk of death in elderly patients treated for dementia-related psychosis (primarily cardiovascular events or infections) [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. Evidence of efficacy includes a pooled analysis of two 12-week randomized trials that compared quetiapine with placebo in mixed-age manic patients [16]. In the subgroup of 59 older patients, symptoms improved significantly more with quetiapine (modal dose 550 mg per day) than placebo. This was consistent with the finding that quetiapine was superior to placebo in younger patients. Among older patients, withdrawal from treatment due to adverse effects occurred in more patients who received quetiapine than placebo (25 versus 10 percent). Olanzapine Olanzapine is usually started at 2.5 to 5 mg once daily in elderly bipolar patients [18,33]. The dose is then increased every two to five days by increments equal to the starting dose, to reach the target dose of 5 to 15 mg per day. For patients who neither respond to 15 mg per day nor are troubled by side effects, the dose may be increased up to 20 mg per day. Olanzapine can cause sedation and falls, as well as weight gain, dyslipidemia, and hyperglycemia [1]. In addition, second-generation antipsychotics are associated with an increased risk of death in elderly patients treated for dementia-related psychosis [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. Evidence of efficacy includes a pooled analysis of three randomized trials (61 acutely manic older patients) lasting three weeks, which found that symptoms improved more with olanzapine than placebo (not tested statistically) [32]. This is consistent with the finding that olanzapine is efficacious in younger patients [35].
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Lithium Lithium is usually started at 150 mg once or twice daily in elderly bipolar patients and increased every one to five days as tolerated [33,36,37]. The half-life of lithium increases to approximately 28 to 36 hours as patients get older; elderly patients thus generally require smaller doses to reach and maintain a steady serum level than do younger patients. The target dose is determined by 12-hour serum trough levels that should be drawn five to seven days after each dose increase. Target doses greater than 900 to 1200 mg per day are rarely required, and some patients 80 years or older may have therapeutic lithium levels with doses as low as 225 to 300 mg per day. A study of 56 geriatric bipolar patients who recovered from their mood episode with lithium found that the mean daily dose was 689 mg [18]. Lithium serum concentrations and laboratory testing are discussed separately. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium dose and serum concentrations' and "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Laboratory tests and monitoring'.) The elderly are at greater risk for lithium toxicity than younger patients. Absorption of lithium is usually not changed by aging, but excretion is typically less in the elderly because the glomerular filtration rate is decreased [36]. In addition, older patients generally have a low volume of lithium distribution caused by reductions in lean body mass and total body water. Lithium side effects observed in older bipolar patients include ataxia, tremor, cognitive impairment, gastrointestinal distress, weight gain, polyuria, polydipsia, peripheral edema, hypothyroidism, rash, and worsening of arthritis [1]. Additional information about lithium toxicity and side effects is discussed separately. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects", section on 'Lithium toxicity'.) Drug-drug interactions involving lithium can increase the risk of adverse effects and toxicity because lithium has a narrow therapeutic index. Specific interactions of lithium with other medications may be determined by using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions. Evidence of efficacy includes a review of four open-label studies (137 geriatric bipolar patients) that found mania improved in 66 percent of patients treated with lithium [21]. Valproate (Divalproex) Valproate is usually started at 125 to 250 mg per day in elderly bipolar patients and increased by the same amount every one to five days [36]. The target dose is generally determined by 12-hour serum trough levels of both total and free valproate, which should be drawn two to five days after each dose increase. We suggest that valproate be dosed to achieve a total serum level of 65 to 100 mcg/mL, although some elderly will not tolerate the higher ranges [38,39]. The half-life and free-plasma fraction of valproate may increase with age [21], and elderly patients generally require smaller doses to reach and maintain a steady serum level than do younger patients. The target dose is generally 500 to 1500 mg per day [33,36]. In a study of 76 geriatric bipolar patients who recovered from their mood episode with valproate, the mean daily dose was 956 mg per day [18]. Common side effects in older geriatric bipolar patients include gastrointestinal distress, sedation, weight gain, and hand tremor [40,41]. Additional information about valproate side effects is discussed separately. (See "Pharmacology of antiepileptic drugs", section on 'Valproate'.) Evidence of efficacy includes a review of five open-label studies (137 geriatric bipolar patients) that found mania improved in 59 percent of patients treated with valproate [21]. In addition, a post-hoc, pooled analysis of three randomized trials lasting three weeks found that in 45 acutely manic older patients, symptoms improved more with valproate than placebo (not tested statistically) [32]. For geriatric bipolar patients who do not respond to treatment with one first-line medication within four weeks of reaching the target dose, or do not tolerate the drug, we suggest tapering and discontinuing the failed medication over one to two weeks at the same time that another first-line medication is started and titrated up. (Response is defined as substantial improvement in the number, intensity, and frequency of symptoms.) The failed medication is
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generally tapered by the same amount for each dose decrease. As an example, quetiapine 300 mg per day is decreased by 50 mg per day, every one to three days. Resistant patients Geriatric manic, hypomanic, and mixed episodes often do not respond to treatment with two to four monotherapy trials of first line medications [16,21,32]. For these resistant patients, we suggest combining lithium or valproate with a second-generation antipsychotic for four weeks, based upon randomized trials in mixed-age adults [28,42,43]. However, lithium plus valproate is a reasonable alternative [44,45]. We generally use a medication combination consisting of: Lithium plus quetiapine or olanzapine, or Valproate plus quetiapine or olanzapine However, there is no evidence of superior efficacy for any specific combination in treating manic, hypomanic, or mixed episodes. Selecting a combination is thus guided by side effect profiles, potential drug-drug interactions, comorbid general medical conditions, patient preference, and cost. Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions. For resistant geriatric bipolar patients receiving lithium or valproate monotherapy for a manic, hypomanic, or mixed episode, we add quetiapine or olanzapine to their regimen. For resistant patients receiving quetiapine or olanzapine monotherapy, we add lithium or valproate to their regimen. The dose and side effects of lithium, valproate, quetiapine, and olanzapine are discussed separately. (See 'First line medications' above.) Resistant geriatric bipolar patients who do not respond to or tolerate one medication combination should be treated with a second medication combination. Generally, lithium is switched to valproate or vice versa. As an example, for patients who do not respond to lithium plus quetiapine or olanzapine within four weeks of reaching target doses, we suggest tapering and discontinuing lithium at the same time that valproate is started and titrated up. Lithium is generally tapered over one to two weeks by the same amount for each dose decrease (eg, lithium 900 mg per day is decreased by 300 mg per day, every one to three days). Conversely, for resistant geriatric patients who do not respond to valproate plus quetiapine or olanzapine within four weeks of reaching target doses, we suggest tapering and discontinuing valproate at the same time that lithium is started and titrated up. Valproate is generally tapered over one to two weeks by the same amount for each dose decrease (eg, valproate 1000 mg per day is decreased by 250 mg per day, every one to three days). Although the antipsychotic (quetiapine or olanzapine) is generally continued at the same dose when lithium is switched to valproate (or vice versa), it is also reasonable to switch the antipsychotic after lithium has been switched to valproate (or vice versa). The antipsychotic is generally tapered over one to two weeks by the same amount for each dose decrease (eg, olanzapine 15 mg per day is decreased by 5 mg per day, every one to three days), and at the same time, the other antipsychotic is started and titrated up. For resistant geriatric bipolar patients who do not tolerate medication combinations, we suggest monotherapy with aripiprazole, risperidone, or ziprasidone [18,33,46]: Aripiprazole Starting dose 2.5 to 5 mg once daily Target dose 5 to 15 mg once daily Maximum dose 30 per day Risperidone Starting dose 0.5 to 1 mg once daily or in two divided doses Target dose 1 to 4 mg once daily or in two divided doses Maximum dose 6 mg per day
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Ziprasidone Starting dose 20 mg once daily or 40 mg per day in two divided doses Target dose 80 to 120 mg per day, in two divided doses Maximum dose 160 mg per day To reach the target dose of aripiprazole, risperidone, or ziprasidone, we suggest increasing the drug every two to five days by increments equal to the starting dose. At the same time, both drugs of the failed regimen are concurrently tapered and discontinued over one to two weeks. Each failed medication is decreased by the same amount each time the dose is decreased. As an example, if the patient is receiving lithium 900 mg per day and olanzapine 10 mg per day, lithium is decreased by 300 mg per day every one to three days, and olanzapine by 5 mg every one to three days. Second-generation antipsychotics are associated with an increased risk of death in elderly patients treated for dementia-related psychosis [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. Information about other side effects of aripiprazole, risperidone, and ziprasidone are discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania", section on 'Second-generation'.) Refractory patients Based upon clinical experience, geriatric manic, hypomanic, and mixed episodes generally respond to treatment with first-line medications or a medication combination. However, for refractory patients whose manic or mixed episode does not respond to four to eight medication trials, we suggest electroconvulsive therapy (ECT) [1,24]. ECT is generally safe and there are no absolute contraindications, even in patients whose general medical status is compromised [47]. However, safety concerns regarding ECT necessitate preprocedure medical consultation. Adverse effects include cardiopulmonary events, aspiration pneumonia, fractures, dental and tongue injuries, headache, nausea, and cognitive impairment. Medical consultation prior to ECT is discussed separately. (See "Medical consultation for electroconvulsive therapy".) Electrode placement and other aspects of ECT technique for treating geriatric bipolar disorder have not been standardized. Thus, ECT is typically administered with the same technique used for other indications and is generally given three times per week on alternating days. Most patients regardless of indication remit with 6 to 12 treatments, but some patients may require 20 or more. Additional information about ECT is discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Technique for performing electroconvulsive therapy (ECT) in adults".) Although there is little evidence for the antimanic efficacy of ECT in geriatric patients [1], several studies suggest that ECT is effective for mixed-age manic patients [48]. As an example, a review (mostly retrospective studies) found that among 589 manic patients treated with ECT, marked improvement occurred in 80 percent [49]. A reasonable alternative to ECT for refractory geriatric mania, hypomania, or mixed episodes is a trial with a firstgeneration antipsychotic, carbamazepine, levetiracetam, or clozapine. However, adverse effects often limit their use [21,36]. Among first-generation antipsychotics, we suggest haloperidol, which is started at a dose of 0.5 to 2.0 mg daily, and increased every three to five days by the same amount to a target dose of 5 mg daily, and a maximum of 10 mg per day. Compared with second-generation antipsychotics, first-generation antipsychotics are more likely to cause extrapyramidal symptoms (EPS) and tardive dyskinesia, and their incidence increases with age [24]. In addition, first-generation antipsychotics are associated with an increased risk of death in elderly patients treated for dementia-related psychosis [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. Evidence for the efficacy of haloperidol includes a multiple treatments meta-analysis of randomized trials in mixed-age patients with a manic or mixed episode; haloperidol was more effective than any other antimanic agent [31]. Additional information about the dose and side effects of first-generation antipsychotics is discussed separately. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Side effects'.)
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Carbamazepine is started at 100 mg once or twice per day, and is increased every three to five days by the same amount [33,36]. The target dose is generally determined by 12-hour serum trough levels that should be drawn three to five days after each dose increase. Based upon clinical experience, we suggest that carbamazepine be dosed to achieve a serum level of 4 to 12 mcg/mL, which is typically achieved with a dose of 400 to 800 mg per day in two divided doses. A study of 12 geriatric bipolar patients who recovered from their mood episode with carbamazepine found that the mean daily dose was 608 mg per day [18]. Adverse effects in geriatric bipolar patients include sedation, ataxia, blurred vision, nystagmus, and leukopenia, or more rarely agranulocytosis [36]. Additional information about the side effects of carbamazepine is discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) Levetiracetam may possibly benefit geriatric bipolar patients with refractory mania, hypomania, or mixed episodes. A case series of six geriatric bipolar patients found that adjunctive levetiracetam (median dose 500 mg per day) improved manic symptoms and was well tolerated [50]. Another alternative to ECT for geriatric patients with refractory manic, hypomanic, or mixed episodes is clozapine. The usual starting dose is 12.5 or 25 mg per day, which is increased by the same amount every day to 25 mg twice per day. Subsequently, the dose is increased by 25 mg per day every day as tolerated, to a target of approximately 150 mg twice per day. One concern with clozapine in elderly patients is fall risk related to sedation and postural hypotension. In addition, second-generation antipsychotics are associated with an increased risk of death in elderly patients treated for dementia-related psychosis [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. In addition, clozapine can cause agranulocytosis and white blood cell counts need to be monitored. Evidence of its efficacy includes a case series of three refractory manic, geriatric patients who responded to clozapine (25 to 112.5 mg per day) [51]. Additional information about the pharmacology of clozapine, including side effects, is discussed separately. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Clozapine'.) Bipolar major depression Geriatric bipolar major depression is typically treated with pharmacotherapy because it is easier to administer, more widely available, and more acceptable to patients compared with electroconvulsive therapy (ECT). However, refractory patients may benefit from ECT. First-line treatment We suggest quetiapine as first-line treatment for geriatric bipolar depression [52,53], based upon analyses of results for geriatric patients enrolled in randomized trials conducted with mixed-age adult bipolar patients (18 to 65 years) [17]. Clinicians can expect that approximately 40 to 50 percent of patients will respond to quetiapine, based upon study results [17]. In elderly bipolar patients, quetiapine is usually started at 12.5 to 25 mg once daily or 25 to 50 mg per day in two divided doses [18,33]. The dose is then increased every two to five days by increments equal to the starting dose to reach the target dose of 100 to 300 mg per day, taken in two divided doses. For patients who neither respond to 300 mg per day nor are troubled by side effects, the dose may be increased up to 600 mg per day [17]. In geriatric patients with bipolar major depression, quetiapine commonly causes dry mouth, sedation, dizziness, constipation, dyslipidemia, hyperglycemia, and weight gain [1,17]. In addition, second-generation antipsychotics are associated with an increased risk of death (primarily cardiovascular events or infections) in elderly patients treated for dementia-related psychosis [34]; some authorities believe this risk may extend to late-life bipolar disorder [24]. Evidence of efficacy includes a pooled analysis of two, eight-week randomized trials that compared quetiapine with placebo in mixed-age patients with bipolar major depression [17]. In the subgroup of 72 older patients, remission occurred more often with quetiapine 300 or 600 mg per day than placebo (45 and 48 versus 28 percent of patients). Although the differences between active treatment and placebo were not statistically significant, the results were consistent with the finding in younger patients that remission occurred significantly more often with quetiapine 300 or 600 mg than placebo. Among the older patients, withdrawal from treatment was comparable for quetiapine 300 mg per day and placebo (29 versus 30 percent of patients), but was greater for quetiapine 600 mg per day than placebo (48 versus 30 percent). Treatment resistance Geriatric bipolar major depression often does not respond to treatment with quetiapine [17]. For these resistant patients, we suggest switching to a second-line drug regimen, consisting of
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lamotrigine, fluoxetine plus olanzapine, lithium, or valproate [1,24,54-60]. No head-to-head trials have compared the efficacy of these drugs for treating geriatric bipolar depression. The choice thus depends upon prior response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. To switch drugs, quetiapine is tapered and discontinued over one to two weeks while at the same time a new drug regimen is started and titrated up. We generally taper quetiapine by the same amount for each dose decrease. As an example, quetiapine 300 mg per day is decreased by 50 mg per day, every one to three days. The starting dose of lamotrigine in elderly bipolar patients is 25 mg per day for two weeks [33,61]. The dose is then increased to 25 mg twice daily for the next two weeks. Thereafter, the dose can be increased by 25 to 50 mg per day, one week at a time for each increase. This slow titration reduces the risk of serious and life-threatening skin rashes, such as Stevens-Johnson syndrome. The target dose is usually 100 to 200 mg per day, taken in two divided doses. A study of 41 geriatric bipolar patients who recovered from their mood episode with lamotrigine found that the mean daily dose was 163 mg per day [18]. Evidence for the efficacy of adjunctive lamotrigine (mean daily dose 151 mg per day) includes a 12-week, open-label study in 57 geriatric patients with bipolar major depression [61]. Baseline depressive symptoms and psychosocial functioning improved significantly and remission occurred in 57 percent. Withdrawal from treatment due to adverse events occurred in 11 percent; side effects included benign rash, reduced or increased sleep duration, weight loss or weight gain, fatigue, and unsteady gait. Fluoxetine plus olanzapine can efficaciously treat bipolar major depression [62]. A randomized trial (N = 437 mixed-age adults) found that remission occurred in more patients who received fluoxetine plus olanzapine than placebo (49 versus 25 percent) [54]. For geriatric patients, we suggest starting fluoxetine at 10 mg per day and increasing the dose by the same amount every four weeks, to a target dose of 20 mg per day. Possible side effects include sedation, insomnia, weight loss or weight gain, abnormal bleeding, bone loss, and fractures. Given its long half life, fluoxetine should be used carefully in older adults. Although use of other antidepressants is not supported by high-quality evidence, we have successfully used either escitalopram 10 to 20 mg per day or venlafaxine 37.5 mg to 225 mg per day. The dose and side effects of olanzapine are discussed elsewhere in the topic, and additional information about fluoxetine is discussed separately. (See 'First-line treatment' above and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".) Lithium [57] and valproate [55] can each effectively treat geriatric bipolar major depression. The dose and side effects of lithium and valproate are discussed elsewhere in this topic. (See 'First line medications' above.) For geriatric bipolar depression that does not respond to treatment with one second-line medication regimen within four to eight weeks of reaching the target dose, we suggest tapering and discontinuing the failed regimen over one to two weeks at the same time that another second-line regimen is started and titrated up. The failed regimen is generally tapered by the same amount for each dose decrease. As an example, lamotrigine 150 mg per day is decreased by 50 mg per day, every one to three days. For patients who discontinue fluoxetine plus olanzapine, both drugs are tapered concurrently. Refractory major depression Geriatric bipolar major depression often does not respond to pharmacotherapy [17,55,61]. For refractory patients whose depression does not respond to three to five medication trials, we suggest electroconvulsive therapy (ECT) [24,63,64]. ECT is discussed separately. (See 'Refractory patients' above.) Although an open-label study with 20 geriatric bipolar patients suggested that adjunctive aripiprazole may possibly improve depressive symptoms [65], we generally do not use it. Two randomized trials in mixed-age adults (N = 374 and 375) with bipolar major depression each found that remission with aripiprazole monotherapy was no better than placebo, and that aripiprazole caused more akathisia, insomnia, nausea, fatigue, restlessness, and dry mouth [66]. Cognitive impairment Cognition is commonly impaired in euthymic, geriatric bipolar patients [67,68]; however, no treatments have demonstrated any benefit. A case series of 12 euthymic, elderly bipolar patients with mild cognitive dysfunction found that adjunctive donepezil did not improve cognition [69]. Cognitive deficits in geriatric bipolar disorder are discussed separately. (See "Geriatric bipolar disorder: Epidemiology, clinical features,
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assessment, and diagnosis", section on 'Cognitive impairment'.) RECOVERY FROM MOOD EPISODES Geriatric bipolar patients generally recover from their mood episodes, and appear to do so more often than younger patients. As an example, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) found that recovery from mood episodes occurred in significantly more geriatric patients than younger patients (78 versus 67 percent) [18]. Geriatric bipolar disorder with late-onset (age 50 years or more) may have a better short-term course of illness than earlier-onset bipolar disorder that has persisted into later life [70]. An observational study found that time to remission of manic or mixed episodes was significantly shorter for 141 late-onset patients compared with 323 earlier-onset patients (40 versus 56 days) [71]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (See "Patient information: Bipolar disorder (The Basics)" and "Patient information: Reducing the costs of medicines (The Basics)".) Beyond the Basics topics (See "Patient information: Bipolar disorder (manic depression) (Beyond the Basics)" and "Patient information: Reducing the costs of medicines (Beyond the Basics)".) These educational materials can be used as part of psychoeducational psychotherapy. (See "Bipolar disorder in adults: Maintenance treatment", section on 'Psychoeducation'.) The National Institute of Mental Health also has educational material explaining the symptoms, course of illness, and treatment of bipolar disorder in a booklet entitled "Bipolar Disorder," which is available online at the website http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml or through a toll-free number, 866-615-6464. The web site also provides references, summaries of study results in language intended for the lay public, and information about clinical trials currently recruiting patients. More comprehensive information is provided in many books written for patients and family members, including The Bipolar Disorder Survival Guide: What You and Your Family Need to Know, written by David J. Miklowitz, PhD (published by The Guilford Press, 2002); An Unquiet Mind: A Memoir of Moods and Madness, written by Kay Jamison, PhD (published by Random House, 1995); and Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by RM Post, MD, and GS Leverich, LCSW (published by Norton Press, 2008). The Depression and Bipolar Support Alliance (http://www.dbsalliance.org or 800-826-3632) is a national organization that educates members about bipolar disorder and how to cope with it. Other functions include increasing public awareness of the illness and advocating for more research and services. The organization is administered and maintained by patients and family members, and has local chapters. The National Alliance on Mental Illness (http://www.nami.org or 800-950-6264) is a similarly structured organization devoted to education, support, and advocacy for patients with any mental illness. Bipolar disorder is one of their priorities. SUMMARY AND RECOMMENDATIONS The minimum age used to define geriatric bipolar disorder is generally 50 to 60 years. The clinical features of geriatric bipolar disorder differ from those of younger patients in that cognitive impairment and comorbid general medical illnesses are more common in geriatric patients, whereas comorbid anxiety and substance
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use disorders are less common in geriatric patients. (See 'Definition' above and "Geriatric bipolar disorder: Epidemiology, clinical features, assessment, and diagnosis", section on 'Clinical features'.) Pharmacotherapy for geriatric bipolar disorder generally requires starting the drug at a low dose, increasing the drug by small increments that are separated by one to seven days, and caution regarding side effects. (See 'Pharmacologic issues' above.) For geriatric patients with an acute manic, hypomanic, or mixed episode, we suggest monotherapy with quetiapine, olanzapine, lithium, or valproate, rather than other medications (Grade 2B). The specific choice depends upon past response to medications, side effect profiles, comorbid general medical illnesses, potential for drug-drug interactions, patient preference, and cost. (See 'First line medications' above.) For geriatric manic, hypomanic, or mixed episodes that do not respond to quetiapine, olanzapine, lithium, or valproate, we suggest combining lithium or valproate with quetiapine or olanzapine, rather than other medication regimens (Grade 2C). (See 'Resistant patients' above.) For geriatric patients with bipolar major depression, we suggest initial treatment with quetiapine rather than other drugs or ECT (Grade 2B). (See 'First-line treatment' above.) For treatment of geriatric bipolar major depression that does not respond to quetiapine, we suggest lamotrigine, olanzapine plus fluoxetine, lithium, or valproate, rather than other drugs (Grade 2C). (See 'Treatment resistance' above.) For geriatric patients with mania or a mixed episode that is refractory to treatment with four to eight medication trials, and for patients with refractory bipolar major depression that is refractory to three to five medication trials, we suggest electroconvulsive therapy (ECT) rather than additional pharmacotherapy trials (Grade 2B). (See 'Refractory patients' above and 'Refractory major depression' above.) Geriatric bipolar patients appear to recover from their mood episodes more often than younger patients. (See 'Recovery from mood episodes' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 16446 Version 6.0
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GRAPHICS DSM-IV-TR diagnostic criteria for major depression

A. Five (or more) of the following symptoms have been present during the same 2-week period, and represent a change from previous functioning. At least one of the symptoms is either depressed mood or loss of interest or pleasure.
(Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations.) Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in children and adolescents) Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day Significant weight loss while not dieting, weight gain, or decrease or increase in appetite Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of substance or a general medical condition. E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, Washington, DC 2000.
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DSM-IV-TR diagnostic criteria for mania

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The symptoms do not meet criteria for a mixed episode. D. The mood disturbance 1) is sufficiently severe to cause marked impairment in occupational functioning, usual social activities, or relationships with others, 2) necessitates hospitalization to prevent harm to self or others, or 3) has psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.
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DSM-IV-TR diagnostic criteria for hypomania

A. A distinct period of persistently elevated, expansive, or irritable mood, lasting at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode 1) is not severe enough to cause marked impairment in social or occupational functioning, 2) does not necessitate hospitalization, and 3) does not have psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg, medication, ECT, light therapy) should not count toward a diagnosis of bipolar II disorder.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.
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PHQ-9 depression questionnaire

Name:
Over the last two weeks, how often have you been bothered by any of the following problems? Little interest or pleasure in doing things Feeling down, depressed, or hopeless Trouble falling or staying asleep, or sleeping too much Feeling tired or having little energy Poor appetite or overeating Feeling bad about yourself, or that you are a failure, or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching television Moving or speaking so slowly that other people could have noticed? Or the opposite, being so fidgety or restless that you have been moving around a lot more than usual Thoughts that you would be better off dead or of hurting yourself in some way Total ___ = ___ + ___ + ___ + ___ 0 1 2 3 0 1 2 3 0 1 2 3 0 0 0 0 0 0 1 1 1 1 1 1
Date:
Not at all Several days More than half the days 2 2 2 2 2 2 3 3 3 3 3 3 Nearly every day
PHQ-9 Score 10: Likely major depression. Depression score ranges: 5 to 9: mild 10 to 14: moderate 15 to 19: moderately severe 20: severe If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people? Not difficult at all ___ Somewhat difficult ___ Very difficult ___ Extremely difficult ___
PHQ-9 is adapted from PRIME MD TODAY, developed by Drs Robert L. Spitzer, Janet B.W. Williams, Kurt Kroenke, and collegues, with an educational grant from Pfizer Inc. For research information, contact Dr Spitzer at rls@columbia.edu. Use of the PHQ-9 may only be made in accordance with the Terms of Use available at www.pfizer.com. Copyright 1999 Pfizer Inc. All rights reserved. PRIME MD TODAY is a trademark of Pfizer Inc.
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Geriatric Bipolar Disorder - Acute Treatment PDF

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Geriatric bipolar disorder: Acute treatment

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