Bipolar Disorder: Optimizing Patients’ Quality of Life

ABSTRACT: Bipolar disorder is misdiagnosed—most often as major depression—in a significant number of patients. Misdiagnosis results in unfocused, potentially harmful, and/or delayed treatment and diminished quality of life. Collaborative care is the best approach for patients with bipolar disorder because it provides comprehensive management of all comorbid physical and mental conditions. Important comorbidities, including substance abuse disorder and suicidal tendencies, must be aggressively managed. The guiding principle of drug selection is to match each patient with the pharmacologic regimen that provides an optimal balance of efficacy, tolerability, and safety. Mood stabilizers—including atypical antipsychotic agents—are first-line therapy; antidepressants, if considered, should not be prescribed without a mood stabilizer. ________________________________________________________________________________________________________________ Bipolar disorder dramatically affects a patient’s health-related quality of life, physical and social functioning, and work productivity. In the United States, the lifetime prevalence of bipolar spectrum disorders is about 6.4%.1 Subthreshold cases are at least 5 times more prevalent than the Diagnostic and Statistical Manual of Mental Disorders–based core syndromal diagnoses (which have a prevalence of 1%). In the primary care setting, about 20% to 30% of patients who present with depressive or anxiety-related illness have bipolar disorder.2  Yet this condition is significantly underrecognized and undertreated. A recent study of 600 patients with bipolar disorder found that their condition was misdiagnosed 69% of the time.3  Bipolar disorder was misdiagnosed as depression 60% of the time, and a mean of 4 physicians were consulted before the correct diagnosis was made. Bipolar disorder manifests relatively early in life—usually before age 25—but accurate diagnosis often lags significantly. Delayed diagnosis may add years of unnecessary hardship and increases the risk of suicide. Proper diagnosis results in access to a variety of treatment measures that are currently available. Effective treatment can enhance quality of life by ensuring that all the parameters of a patient’s condition are optimally addressed. In this article, I discuss the role of the primary care physician in the management of bipolar disorder and review guiding principles that help provide optimal outcomes and enhanced quality of life. BIPOLAR DISORDER AND PRIMARY CARE Primary care is the “de facto” setting for mental health care. A new study shows that although the prevalence of mental disorders did not change between 1990 and 2003, an increase of more than 150% in the treatment rate was seen in the sector of general medical services.4 The prevalence of mental distress or mental illness in primary care waiting rooms is significant, particularly among frequent users of medical care.5 It comes as no surprise, therefore, that primary care physicians are major prescribers of antidepressants and other psychotropic agents. Because many of these medications (such as the selective serotonin reuptake inhibitors) have a good safety profile, and because in many instances time is limited, it is tempting to add a second or even third antidepressant if a depressed patient is not responding to antidepressant monotherapy. The concern in this situation is that in many cases, the illness being treated has not been diagnosed correctly. Making the diagnosis. As with physical disorders, differential diagnosis is the key to appropriate treatment of mental disorders, and it must precede the initiation of drug therapy. For example, a patient who is wheezing may not necessarily have asthma but may have pulmonary edema. Prescribing an asthma medication would be inappropriate and potentially harmful. Similarly, a patient who is depressed may have a unipolar major depression or a specific anxiety disorder—or he or she may have bipolar disorder. For certain patients with bipolar disorder, antidepressant monotherapy may have catastrophic results, including the development of mania/ hypomania, mixed states (and their attendant increase in suicide risk), rapid cycling, and treatmentrefractory states. Without a focused, accurate diagnosis, we cannot prescribe the most beneficial therapy and we may sometimes prescribe harmful therapy. Treatment may become “trial and error,” involving dose increases or combinations of antidepressants that fail to produce a stable response. In any case, suffering is prolonged and recovery delayed. Every patient with a tentative diagnosis of depression who does not respond adequately to an antidepressant must be reevaluated for other forms of psychopathology, including bipolar disorder. In addition to the difficulty of differentiating bipolar depression from unipolar major depression, the clinical picture may be clouded by other psychiatric comorbidities—including substance abuse disorders, anxiety disorders, and eating disorders—thereby distracting the clinician from a complete and accurate diagnosis. For example, among persons with an established borderline personality disorder diagnosis, the presence of comorbid bipolar disorder may be high. Current somatic treatment approaches for patients with borderline personality disorder emphasize agents with proven efficacy as mood stabilizers. Establishing treatment goals. Once a diagnosis of bipolar disorder has been made by a primary care physician, he or she must decide the level of involvement desired and establish treatment goals based on the practice setting: • Immediate referrals: If a patient is in acute danger to himself or others, referral is the appropriate next step. However, there may be a considerable time lapse before he can be seen by a specialist. Therefore, stabilization by the primary care physician is mandatory. • Patients who can be referred: These patients do not need immediate referral, but do need to be transitioned to a psychiatrist. An appropriate shortterm treatment plan—including medication—is required. • Patients who will not be referred: The primary care physician must establish short-term and long-term treatment goals. Candidates for referral—in addition to patients who are a danger to themselves or others—include those whose diagnosis is unclear, whose symptoms are refractory to treatment, who require intensive outpatient therapy, or who are deemed poor matches for individual clinicians. ENHANCING CARE FOR OPTIMAL QUALITY OF LIFE The therapeutic alliance. For patients with bipolar disorder, care is best delivered via a therapeutic alliance—that is, a collaborative, sharedcare relationship between the patient and all of his caregivers, including the psychiatrist, psychologist, case manager, pharmacologist, social worker, and primary care physician. An open, ongoing dialogue with other team members is vital for optimal patient care. The primary care physician may choose to stay involved with the patient for the sake of continuity and to treat any comorbid disorders, such as diabetes or hypertension, while the psychiatrist takes primary responsibility for the bipolar disorder. The value of primary care in the treatment of these complex illnesses should not be underestimated. Primary care physicians are often more available than their colleagues in the specialty mental health sector and have the advantage of a broad frame of reference for biopsychosocial illness. Patient education. Educating all partners in the therapeutic alliance—including the patient and his family—is a vital step. It is imperative for patients and their families to know that bipolar disorder has a genetic component and that it is a chronic, lifelong condition that requires long-term management. Numerous Web sites and other resources exist. Optimizing overall health. Medical conditions are generally more severe in patients with mental illness than in those without mental illness. For example, the best predictor of early mortality after myocardial infarction is not left ventricular function or ejection fraction but depression.6 Depression has also been found to increase mortality among patients with asthma and diabetes.7,8  Aggressive treatment of mental illness may contribute significantly to better physical health. Monitoring and managing. Primary care physicians are in the best position to keep track of the “big picture” for each patient (Table 1). They can ensure that routine health maintenance and risk factor assessment are not overlooked in the focus on the patient’s mental illness. For example, women with bipolar disorder should be queried about sexual activity and, if warranted, screened more closely for cervical cancer. Patients with bipolar disorder are much more likely than those without the disorder to have the metabolic syndrome or diabetes. They are also more likely to have a psychiatric comorbidity, such as social anxiety disorder or panic disorder. Primary care clinicians can also add value to shared care by monitoring treatment for efficacy and tolerability. You can be alert to drug-drug interactions, adverse effects, and impact of treatment on psychiatric or medical comorbidities. You can encourage compliance. You can be on the lookout for early signs of escalating illness severity. You can also encourage patients to “invest” their improvement in behaviors that enhance overall health, such as exercise/weight control, smoking cessation, and community activities. The advantages of collaborative care. Preliminary data show that the advantages of collaborative care are significant. In one study, depressed elderly patients in a collaborative care group experienced greater relief of symptoms, less impairment, and better quality of life in acute phase interventions.9  In another trial, collaborative care patients with persistent depressive symptoms demonstrated improved adherence and satisfaction with care and greater relief of depressive outcomes beyond the acute phase, compared with patients who received usual care.10 TREATING MAJOR COMORBIDITIES The frequency of psychiatric comorbidities in patients with bipolar disorder is extremely high (Table 2). It is imperative that these comorbidities— especially such serious conditions as substance abuse—be treated effectively. Early recognition and treatment will significantly improve the quality of life of patients with these disorders. Substance abuse. The effects of substance abuse on bipolar disorder are listed in Table 3. Substance abuse and dependency rates are higher in bipolar disorder than they are in any other Axis I disorder. Substance abuse disorders may contribute to delayed diagnosis of bipolar disorder; they increase both the severity of the bipolar disorder and the suicide risk and may contribute to poorer treatment response. In susceptible persons, such as those with a family history of bipolar disorder, drug use appears to contribute to earlier onset and greater severity of symptoms. Patients with comorbid substance abuse and bipolar disorder require expert management of both disorders. Improvement in mood does not automatically lead to decreased substance abuse. Primary care physicians who treat patients with bipolar disorder and a comorbid substance abuse disorder have an important opportunity to educate patients about the dangers of their condition, the effects of substance abuse on bipolar symptoms, and the necessity for aggressive treatment of both conditions for improved quality of life. Pharmacologic principles. Few empirically derived data exist for the management of comorbid bipolar and substance abuse disorders. Integrated treatment is likely to be more effective than sequential or parallel treatment in these patients. A recent study of patients with this comorbidity who underwent integrated treatments found that during a 3-year follow-up period, there was a 61% remission rate for substance abuse. Patients also improved on measures of independent living, competitive employment, regular social contacts with non–substance abusers, and quality of life.11 I use mood stabilizers or drugs with mood-stabilizing properties (ie, the atypical antipsychotics) as first-line therapy to ensure that bipolar disorder is addressed, no matter what the phase of illness. Parallel treatment with psychotherapy, chemical dependency rehabilitation, and medical therapy for other comorbid conditions should be initiated at the same time. Once mood is under control, any remaining comorbidities should be identified and addressed. Avoid using stimulants, antidepressants, and benzodiazepines initially. Suicide. The number of expected versus observed deaths from all causes is significantly higher in patients with bipolar disorder (Figure) than in persons without the disorder—and a disproportionate number of the additional deaths are from suicide. Approximately 25% to 50% of persons with bipolar disorder attempt suicide during their lifetime; this is more than 20 times the rate in the general population. About half of all suicides can be attributed to bipolar disorder. Persons with bipolar disorder attempt suicide twice as often as those with unipolar depression and are more likely to use lethal means. Suicide risk is greater during depressed and mixed states than during mania, and it is doubled in the presence of substance abuse.12-14 Figure – The graph shows expected versus observed deaths in a population of patients with bipolar disorder.13,24 The good news is that proper treatment has profound effects. In a study of more than 400 patients hospitalized for mood disorders who were observed for about 35 years, the suicide rate among treated bipolar patients was 6.4%; among untreated patients, it was 29.2%.15  This significant improvement was achieved even though the treated patients were more severely ill. Patients whose mood disorder was treated also had lower mortality rates in other areas, including neoplasms, cardiovascular causes, cerebrovascular causes, and accidents. In a patient who has attempted suicide, the first diagnosis to consider is bipolar disorder. Unfortunately, patients who have attempted suicide frequently do not receive a prompt diagnosis. One study found that if a patient presented for psychiatric treatment after a suicide attempt, it took 15 years for the proper diagnosis to be established.16  If a patient presented without a suicide attempt, it took 6 years. Risk factors for suicide in bipolar disorder include: • Early age at disease onset. •A high number of episodes of depression. • Comorbid alcohol use. • History of antidepressant-induced mania. • Family history of suicidal behavior. • Traits of hostility and impulsivity. The highest rate of suicide occurs in patients with the greatest degrees of both hopelessness and impulsivity.17  In patients who feel severely depressed and hopeless, any small increase in impulsivity can tip the balance in favor of suicide. This explains why antidepressant-induced mania is a risk factor for suicidality in some severely depressed patients: the antidepressant boosts their energy and impulsivity before it improves their mood. It also explains the high suicide risk in bipolar mixed states, in which the depression sets the tone of the mood state and the comorbid mania supplies dangerous energy and impulsivity. Interestingly, suicide rates are highest in May. This may reflect seasonal increases in exposure to light and, secondarily, psychomotor energy. That suicidality is predominantly a “spring thing” may seem counterintuitive to primary care physicians, who are accustomed to associating suicide with the winter holidays. MAXIMIZING DRUG TREATMENT The guiding principle of drug selection is to match each patient with the pharmacologic regimen that provides an optimal balance of efficacy, tolerability, and safety and that promotes compliance. Other important recommendations are listed in Table 4. Mood stabilizers are first-line therapy for patients with bipolar disorder. Antidepressants are not recommended without a concomitant mood stabilizer. Lithium, divalproex, and carbamazepine ER are effective for the treatment of acute mania. Other forms of carbamazepine may be an acceptable alternative. Predictors of an antimanic and prophylactic response to lithium include typical manic symptoms (such as euphoria and grandiosity) and a family history of bipolar disorder or lithium response. Predictors of success with divalproex or carbamazepine include mixed states (such as pervasive, destructive irritability), rapid cycling, and secondary mania (from antidepressant use). Divalproex may be preferred when comorbid substance abuse is present. Combinations of agents are typically required for robust, sustained response. Many primary care physicians hesitate to use lithium because they fear that it is “dangerous” or believe that it should be prescribed only by psychiatrists. Lithium is very much an underappreciated medication in primary care; at the lower doses usually used these days, it is well tolerated and effective for many patients. However, lithium is not used alone for acute mania because of its relatively slow onset of action; it is generally combined with an atypical antipsychotic, which improves overall efficacy and may allow for lower dosages of lithium (and therefore, better tolerability). Lithium may also be combined with divalproex or carbamazepine. Adverse effects. Possible adverse effects of lithium include neurocognitive, renal, GI, and endocrinologic (eg, hypothyroid) effects and weight gain. Lithium has a narrow therapeutic index and requires periodic blood level monitoring. Divalproex is associated with GI effects and thrombocytopenia (dose-related), weight gain, tremor, sedation, and neural tube defects in pregnant women (first trimester). Delayed-release or extended- release forms are preferred to valproic acid. Carbamazepine may cause such adverse effects as GI symptoms, sedation, ataxia, blurred vision and, rarely, blood dyscrasias. Atypical antipsychotic agents. This group includes aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone, which were initially developed for schizophrenia but are effective antimanic agents. Some agents demonstrate both maintenance and antidepressant effects and have potential as stabilizers. The atypical antipsychotics are generally effective, well tolerated, and straightforward to use. They have not been associated with significant drug-drug interactions and may be combined effectively with antidepressants. A great advantage of the newer antipsychotic agents is that, unlike older antipsychotics, they treat mania without inducing depression. Furthermore, they can be combined with other agents (“rational polypharmacy”) so that complementary mechanisms of action are in play, thus improving patient outcomes. For example, olanzapine may be combined with lithium or divalproex, which may allow for lower doses of both of these agents. For treatment of bipolar depression. There are not as many choices for bipolar depression as for bipolar mania because there are fewer data for bipolar depression—even though most people with bipolar disorder experience it as a depressive illness. Patients with bipolar depression, even those who have been “protected” with a mood stabilizer, may sometimes experience a worsening of symptoms with an antidepressant. This is why it may be preferable to combine mood stabilizers that have antidepressant activity rather than to add antidepressants for patients with bipolar depression. The combination of olanzapine and fluoxetine is the only treatment currently approved for acute bipolar depression. Other atypical antipsychotic agents, such as quetiapine, may eventually be approved for acute bipolar depression. In a recent randomized trial, quetiapine was effective and welltolerated monotherapy.18  It reduced suicidal thoughts, pessimism, lassitude, sadness, and other symptoms of depression. Aripiprazole is indicated for maintenance therapy in bipolar disorder. Lamotrigine, an antiepileptic agent, has been approved for maintenance treatment in bipolar disorder; its principal effect is preventing bipolar depression. There are positive, although limited, data that demonstrate the efficacy of lamotrigine in acute bipolar depression. Adverse events. The possible treatment-associated effects of atypical antipsychotics are listed in Table 5. One of the biggest concerns with some atypical antipsychotics is an increase in appetite, which may lead to worsening obesity. Patients with bipolar disorder tend to gain weight. During depressions, many of these patients are physically inactive and may oversleep. Treatment-associated hyperglycemia and diabetes are also concerns. It is still not known from prospective controlled studies which atypical antipsychotic agents are best avoided in patients with tendencies toward obesity or diabetes. Therefore, all patients treated with these agents must be pre-assessed and monitored, especially during the first 6 months of atypical antipsychotic use. Diabetes is not an absolute contraindication for atypical antipsychotic agents, although patients with diabetes will require the closest monitoring of glycemic control. Anecdotally, once a patient’s mood is stabilized, he may be more likely to take better care of his diabetes and may be more motivated to exercise and adopt other healthy lifestyle measures. Extrapyramidal symptoms and tardive dyskinesia occur infrequently with the use of atypical antipsychotics. They are more likely to be seen in older or very young patients and in those treated at higher rather than lower doses. Patients with Alzheimer disease are at significantly increased risk for cerebrovascular adverse events with most atypical antipsychotic agents. REMISSION: THE GOAL OF TREATMENT Only patients in remission are likely to recover full function.19  Functional recovery may lag behind symptomatic improvement, and rational polypharmacy is often required for robust, sustained response. The combination of medication and psychotherapy often yields the best results.20 According to a recent review, functional outcomes are more meaningful measures of response to treatment of bipolar disorder than are scores on psychiatric rating scales that are used to gauge improvement in symptoms.21  Using functional outcomes as a measure of response, patients are considered to be in remission if they achieve normal or nearnormal levels of functioning in family, social, and occupational settings.  Adherence to therapy is crucial for remission and for optimal quality of life. Failure to adhere to treatment regimens increases the risk of relapse that results in hospital readmission.22 A recent prospective study of patients being treated with mood stabilizers showed that 81% of patients who were partially adherent had at least one admission to a psychiatric hospital, compared with 9% of adherent patients.23 For optimal outcome, emphasis on adherence must be incorporated into the management plan of patients with bipolar disorder. Dr Manning is adjunct associate professor of family medicine at the University of North Carolina School of Medicine. He codirects a mood disorders clinic at the Moses Cone Family Practice Residency in Greensboro, where he also has a private practice. REFERENCES: 1. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J Affect Disord. 2003;73: 123-131. 2. 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