Feature Article
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The pharmacologic treatment of bipolar disorder in older adults presents several challenges. Tolerability of the commonly prescribed medications, interaction with other potentially sedating agents, and the patient’s compliance are important in the selection of medications in the elderly bipolar patient. The elderly patient is more susceptible to electrolyte abnormalities and dehydration while taking lithium salts. Tremors induced by lithium may occur even at normal blood levels of lithium. The anticonvuýsants valproic acid and carbamazepine have become excellent alternatives to lithium. More recently, the atypical neuroleptics, olanzapine, risperidone, and quetiapine, have been used as adjunct therapies, and even as alternatives to the previous mood stabilizers with good results. From a tolerability standpoint, olanzapine has been associated with metabolic side effects such as lipid and glucose abnormalities. Risperidone has been associated with cerebrovascular events and extrapyramidal side effects (EPS). Conversely, quetiapine seems to be effective and to have a safer side-effect profile with only transient sedation, no EPS, and no metabolic changes. The following cases illustrate the successful use of quetiapine in elderly patients with bipolar and schizoaffective disorders.
Case #1
Ms. S is a 69-year-old female with a history of bipolar disorder and seizures who is currently living in an independent apartment. The patient has a long history of mental illness with sporadic hospitalizations. Ms. S was enrolled in a public mental health case management. At her first visit, she was on quetiapine, lithium carbonate, and fluoxetine. Her compliance with medications was always questionable. Ms. S often decreased her medications, including her anticonvulsant phenytoin, because she felt overmedicated. Her lithium level was always low, resulting in mood swings and severe anxiety. She was sleeping poorly and had religious rumination related to “visions” of the devil years before. Her mood was anxious; no formal thought disorder was observed. She was also questionably taking 200 mg of quetiapine 3 times daily and subtherapeutic doses of lithium. We decided to discontinue lithium to encourage her compliance, while stressing the importance of using the other medications as prescribed. We also warned the patient of a possible relapse into mania, but she was quite enthusiastic about the discontinuation of lithium, which she felt was “sedating” her.
Since lithium was discontinued, Ms. S’ compliance has improved significantly, her anxiety is decreased, and she suffers from minimal mood swings. This patient had significant compliance problems with her lithium intake due to sedation and to her refusal to have her lithium and phenytoin blood levels checked, making the management of her psychotropics very difficult. Ms. S has been treated with the same doses of quetiapine 200 mg 3 times daily, fluoxetine 90 mg weekly, and phenytoin 100 mg twice daily for the last 2 years. She has not relapsed into the hospital, and has not suffered from any side effects such as sedation, hypotension, EPS, tardive dyskinesia, or falls.
Case #2
Mr. J is a 65-year-old male with bipolar disorder with recurrent depression and psychotic features. He is currently living in a residential care center. Mr. J has suffered mostly from depressive episodes during the last 10 years. He has remained depressed despite a regimen of three antidepressants, fluoxetine 80 mg per day, mirtazapine 45 mg at bedtime, and divalproex 250 mg in the morning and 1000 mg at bedtime. He has also undergone electroconvulsive therapy (ECT) maintenance monthly. Quetiapine was then added to his regimen in order to decrease his suspiciousness and to prevent the recurrence of manic symptoms. The patient was started on 100 mg at bedtime, which was titrated up 100 mg every 10-15 days to reach the current dose of 100 mg in the morning and 500 mg at bedtime. We were able to significantly improve the paranoia and depression with suicidal ruminations. The patient no longer needs ECT and frequents an intensive psychoeducational day program. Mr. J’s obsessive-compulsive routines, which are usually focused on purchasing watches when visiting the local shopping center, have also decreased. Mr. J remains psychosis-free and mania-free but still has ongoing dysthymic features. Mr. J has been able to socialize and has better control over his suicidal thoughts. For the last 18 months, this patient has required no hospitalization. Furthermore, no signs of sedation have been observed, and the patient is compliant with the treatment plan.
Case #3
Mr. E is a 78-year-old male with a long history of bipolar illness. This patient has been hospitalized repeatedly due to poor compliance with medication. His last admission was precipitated by stopping olanzapine, which he claimed was not helping his poor sleep pattern. Upon admission, the patient was in a manic state: he had not slept for days, he had been aggressive toward his wife, and he was obsessed with the frequency of his bowel movements. Mr. E was placed on a starting dose of quetiapine 50 mg 4 times daily as monotherapy. Within 24 hours, he became significantly calmer, and even experienced some sedation, which led me to change his dose to 150 mg at bedtime only. Seventy-two hours after initiating quetiapine, the patient was no longer manic, but he developed mild signs of depression. He was then started on paroxetine 20 mg at bedtime. For the next 5 days, his medication regimen was not changed. The patient became progressively more social and less preoccupied with his bowel movements. Mr. E did not experience any falls or blood pressure changes. No extrapyramidal symptoms were noted. His appetite and sleep pattern both normalized. He was discharged back to his home. The patient was able to tolerate a rather rapid titration in the dose of quetiapine to successfully ameliorate his acute manic and psychotic features. In addition, an improvement was noted in his somatic preoccupations that had both an obsessive and a psychotic quality.
Case #4
Ms. O, a 55-year-old female with a history of schizoaffective disorder, has been institutionalized most of her adult life. She resides in a residential care facility after being released from a state mental institution. We became involved in her treatment in January 1999. At that time, the patient was on thiothixene 1 mg twice a day, paroxetine 20 mg, buspirone 15 mg 4 times daily, and trazodone 25 mg 4 times daily. Her Abnormal Involuntary Movement Scale (AIMS) score was 12, indicating significant signs of tardive dyskinesia. Clinically, Ms. O was withdrawn, her affect was restricted, she had significant poverty of speech, and she appeared preoccupied with internal thoughts. At times she would become agitated for no reason. We decided to discontinue thiothixene due to tardive dyskinesia consisting of involuntary movements of her fingers and mouth.
Quetiapine 25 mg twice a day was initiated, and the dose was increased in the course of the next year to 50 mg twice a day. Concomitantly, buspirone was decreased to 10 mg 3 times daily, and trazodone was discontinued. During the past 2 years, Ms. O has remained fairly stable. Still withdrawn with blunted affect, she appears less internally preoccupied and has an easier attitude toward others. We have attempted to reduce her quetiapine unsuccessfully due to the reoccurrence of agitation. Her AIMS score has been 0 for the past 2 years, as her orofacial and hand movements are no longer present. She has not required acute psychiatric hospitalization. Her episodes of agitation have been sporadic and have not required as-needed medication. She has gained approximately 10 pounds over the last 2 years. No sedation, falls, or metabolic abnormalities have been observed despite the weight gain. It seems that quetiapine has a positive effect on reducing tardive dyskinesia. In this case the improvement was dramatic.
Case #5
Mr. R is a 64-year-old male with a history of bipolar disorder, depression without psychotic features, and alcoholism. He was referred from his nursing home for hospitalization due to increased depression and refusal of care. The patient had a history of diabetes and osteomyelitis that led to bilateral ankle amputation. Upon admission, he was withdrawn and remained depressed while taking venlafaxine 150 mg twice a day and trazodone 350 mg at bedtime. Mr. R became irritated with the staff at the nursing home and had been refusing his care. The staff felt that he was endangering himself by refusing care and noticed his increasing hopelessness. While in the hospital, Mr. R became suspicious that there was a conspiracy to get his insurance money and to harm him for his refusal to leave his room. We decided to treat his new-onset psychosis with quetiapine 50 mg at bedtime, increasing the dose of 25-50 mg every 3 days up to 200 mg at bedtime. His complaint of insomnia had previously led to the use of large doses of trazodone while in the nursing home. We were able to decrease trazodone to 150 mg at bedtime. Mirtazapine up to 45 mg at bedtime was selected to augment his antidepressant venlafaxine. Mr. R was released to frequent a partial hospitalization program with the goal of increasing his understanding and management of his illness.
Case #6
Mrs. R is a 68-year-old female with a history of bipolar disorder. She presented to the geriatric day program with symptoms of depression concomitant with divorcing her husband and moving to a different town. Her medication included valproic acid 500 mg twice a day and paroxetine controlled-release 50 mg at bedtime. The patient developed symptoms of paranoia with fear of her ex-husband trying to harm her, and she became disorganized in her thinking and suffered from severe anxiety.
Mrs. R was hospitalized, and risperidone 1 mg at bedtime was added to her medications. This resulted in a partial resolution of her psychosis. The patient remained suspicious, complained about the valproic acid causing hair loss, and demanded an alternative mood stabilizer. Topiramate up to 100 mg at bedtime was initiated because the patient informed us she had had a bad reaction to lithium and carbamazepine in the past. Mrs. R unfortunately experienced significant sedation, and topiramate was stopped during her next hospitalization. Despite her alleged good compliance with taking her medications, she experienced a relapse of paranoia, disorganized thinking, and anxiety.
We decided to substitute quetiapine for the valproic acid and risperidone. Quetiapine was started at 25 mg at bedtime for 1 day, then increased to 25 mg per day to reach 200 mg at bedtime in 1 week. Risperidone and valproic acid were titrated off and paroxetine controlled-release was continued at 50 mg at bedtime. During the last few months, Mrs. R’s paranoia has disappeared, her thinking process is remarkably more goal-oriented, and her anxiety has decreased. The patient continues to frequent the day program successfully.
Case #7
Mrs. A is a 70-year-old female with a history of bipolar disorder. She has been stable on sertraline 100 mg at bedtime and olanzapine 5 mg at bedtime. She decided to decrease and then stop her medication, which led to a relapse in paranoid psychosis and severe depressive symptoms. She was hospitalized in a melancholic state; she suffered from delusions, was paranoid toward family and staff, and had a poor appetite. She was placed back on her previous medications, and despite an increase of olanzapine up to 12.5 mg, the patient’s symptoms did not improve. She underwent five ECT sessions with complete resolutions of her psychopathology.
Mrs. A is currently on sertraline 100 mg, and quetiapine 50 mg at bedtime was added to prevent relapse into psychosis and mania. For the last few months, she has been frequenting a geropsychiatric day program. Her insight is good, no depressive/manic symptoms are present, and no psychosis has been noticed.
In this case, we have discovered that quetiapine is effective in the post-ECT maintenance regimen of bipolar depression. So far, lithium has shown the lowest rate of relapse in mood disorders post-ECT. We believe that further studies are necessary to ascertain the efficacy of quetiapine in the long-term approach to mood stabilization.
Case #8
Ms. L, a 72-year-old female with a history of bipolar disorder and Parkinson’s disease, has been living in a nursing home for several years due to the severity of Parkinson’s symptoms, severe tremor, and gait disturbance. The patient is currently on levodopa/carbidopa 25/250 mg 3 times daily, and is no longer ambulatory. Her cognitive status is within normal range. Her psychiatric symptomatology consists of grandiosity, pressured speech, and paranoia. She believes that her ex-husband is a member of the Mafia and wants to harm her, and she often engages in grandiose projects of financial fortunes.
We have been treating Ms. L for several years. We did switch her from lithium to valproic acid 250 mg 3 times a day in order to diminish her tremors. Unfortunately, her psychosis and poor compliance brought her back to the hospital several times over the years. Olanzapine up to 10 mg failed to control the psychosis and the elated-irritable moods persisted. We started quetiapine up to 150 mg with very little result, and then discontinued it. Later we tried risperidone up to 3 mg per day, which controlled the psychosis but produced worsening of Parkinson’s disease with an increase in tremor and cogwheeling to such a degree that risperidone had to be discontinued. We then decided to try quetiapine 50 mg 3 times a day and increased it to 50 mg at a time up to 200 mg 3 times a day. This dosage produced a remarkable control over her psychosis and manic symptoms.
Ms. L was still complaining of feeling sedated, and we then decided to discontinue the divalproex. No relapse of manic symptoms was observed and the grandiose-persecutory delusions are minimal. Ultimately, the patient’s medication regimen was simplified to quetiapine 200 mg 3 times a day. The intensity of her tremor has returned to baseline and she is not experiencing any cogwheeling. The patient continues to complain about being “tired,” but the nurses have not witnessed it. In this case, the patient’s compliance and tolerability were sufficient reasons for attempting a change in her medication regimen, which we feel has allowed a more stable condition. In fact, this patient has not suffered any psychiatric rehospitalization since quetiapine was started.
Discussion
Bipolar disorder is a chronic illness that often presents in early adulthood but persists into late life.1 It is characterized by episodes of mania with elevated, expansive, or irritable mood and symptoms including grandiosity, decreased sleep, increased or pressured speech, flight of ideas, distractibility, increased activity, and excessive involvement in pleasurable activity.2 Psychotic features may accompany a manic episode. Hypomania is an episode of similar symptoms of lesser intensity that do not impair social or occupational functioning. Most patients with bipolar disorder have periods of depression, but the variability among individuals is high. Some patients display predominantly depressive features with periods of hypomania, while others have episodes of predominant mania with depression (Table I).1,2
Bipolar disorder affects men and women equally. The lifetime prevalence of bipolar disorder ranges from 0.8-1.6%. First-degree relatives of patients with bipolar disorder have a significant increase in incidence of the disorder—up to 24%.1,2 Bipolar disorder in late life accounts for up to 20% of admissions to inpatient geriatric psychiatry units.3 This indicates that despite the relatively low prevalence of the disorder in the population, the need for intensive treatment services due to active symptoms is significant. The excess morbidity associated with the disorder is high and recurrent hospitalizations are common.3,4
Late-onset bipolar disorder occurs after age 50, and is more likely to be associated with multiple comorbid medical conditions, medications, and neurologic disorders.5,6 It is less likely to be associated with family history of mood disorders. New-onset manic symptoms in an older adult require a thorough medical evaluation, review of medications, alcohol, and substance use, and attention to possible cerebrovascular events. There are multiple medical causes of mania in late life (Table II).1-3 Older manic patients seldom display the euphoric or elated mood that is characteristic of younger adults, and are more likely to appear irritable, angry, paranoid, and disorganized.1,3
Patients with bipolar disorder are at risk for substance abuse, and the physician should screen for this periodically. Alcohol is the most commonly abused substance among older adults with bipolar disorder, but other drugs including stimulants, benzodiazepines, and marijuana have been used.1 In addition, patients with mood disorders are at an increased risk for the development of dementia.7,8 This often leads to an increase in mood instability, behavioral problems, and inability to perform activities of daily living. Institutional placement may be necessary at an earlier stage of dementia when mood disturbances and behavioral problems become prominent.8
Pharmacotherapy is the mainstay for the treatment of acute mania, as well as maintenance therapy for the prevention of relapse.1,3,4 Mood stabilizers are the treatment of choice for mania, but often require several weeks of titration (Table III).1,4 While mood stabilizers are the principal treatment for bipolar disorder, many elderly patients are unable to tolerate lithium due to neurologic and gastrointestinal side effects. Alternate agents such as valproate, carbamazepine, lamotrigine, and gabape*tin are often ineffective as monotherapy.3,4 The need for both acute and maintenance therapy with antipsychotic agents is increasingly being recognized as effective and well tolerated in older adults with bipolar disorder. Due to the increased incidence of rapid cycling and mixed states of depression and mania in older adults with bipolar disorder, mood stabilizers alone may not allow the patient to reach a stable level of functioning. The addition of atypical antipsychotic agents has been useful in treating psychotic symptoms and providing a mood-stabilizing effect.1,3
Psychotic symptoms are common in bipolar disorder, which shares some of its features with other psychotic disorders including schizophrenia. Thought disorder, recurrent episodes of delusions, and severe behavioral disturbances like physical aggression are common. More than 50% and up to 75% of patients will have at least one psychotic symptom during an episode of mania. The presence of two or more psychotic symptoms occurs in one-third of manic patients. Psychotic symptoms are associated with a higher rate of relapse, a longer duration of symptoms, and a lower probability of returning to a stable baseline.3 Long-term antipsychotic treatment is often required in this population.
Antipsychotic agents have been utilized in the treatment of acute mania to help stabilize symptoms and reduce concurrent psychotic features.9ýAntipsychotic agents are also utilized to help reduce the agitation and aggression that may accompany severe mania. Benzodiazepines are also used as adjunct therapy, but should be time-limited in the elderly due to the risk of falls, fractures, and confusion.1 Antidepressants are often used for the treatment of depressive episodes in bipolar disorder, but there is concern that these agents may precipitate a manic episode.4 Acute mania accompanied by severe psychosis may require ECT if response to medications is poor.1
Atypical antipsychotic agents are the treatment of choice when a neuroleptic is needed, particularly in older adults (Table IV).1,10 The mood-stabilizing effects of atypical agents have been demonstrated in a number of studies.10 The side-effect profile of these agents—particularly the advantage of limited EPS with reduced risk of tardive dyskinesia—has made their use preferable (Figure).11 The risk of tardive dyskinesia persists, but is small; less than 3% per year of treatment with some agents, including quetiapine, is associated with improvement in movement disorders. There remain some concerns regarding elevations in blood glucose, triglycerides, weight gain, sedation, and orthostatic hypotension. These side effects are variable among the individual agents.12
Recent studies have shown that quetiapine is very effective as a single or adjunct agent in treating symptoms of mania.13-15 A short-term study of patients suffering from acute mania revealed that quetiapine up to 800 mg per day (mean dose = 580 mg/day) added to a mood-stabilizer was more effective than either lithium or valproate treatment alone. This is similar to outcomes found with the other atypical agents risperidone, olanzapine, and aripiprazole.10
Two studies have demonstrated the efficacy of quetiapine alone in alleviating the symptoms of acute mania in doses ranging from 200-800 mg per day. The most common side effects seen were somnolence, dry mouth, and postural hypotension, which often resolved with slow titration of the dose.14,15ýStudies have traditionally limited the maximum dose of quetiapine to 800 mg per day. Recent data suggest that doses of quetiapine up to 1300 mg have been both well tolerated and effective, even in an older population in which severe and persistent symptoms are present.16
Quetiapine offers some unique advantages in the treatment of bipolar disorder. It has antimanic effects and a low incidence of EPS.17 The sedating effects of the drug are often desirable in the treatment of acute mania, particularly when sleeplessness and agitated behavior are prominent.18 The sedation diminishes over time, making the agent also suitable for ongoing maintenance treatment. The minimal effects on blood glucose, triglycerides, cardiac rhythm, and weight gain make the agent promising for chronic use.19
ýuetiapine has been useful in the treatment of psychotic symptoms associated with mood disorders, with improvement noted in depressed mood. Patients with a strong mood component often responded rapidly when quetiapine up to 300 mg per day was added to their regimen.20 No worsening of depression was noted, and improvement in both mood and psychosis was maintained, which makes quetiapine useful as monotherapy in cases when minimizing medication regimens is useful, such as in older adults and those with compliance issues.21
Quetiapine has been useful in complex cases, including rapid cycling bipolar disorder, with improvement in both the manic and depressive symptoms of the illness.22 Since older adults are more likely to experience rapid cycling and mixed features during an episode of bipolar disorder, this agent is of particular benefit. The ability to individually titrate the dose to minimize sedation is important, and monitoring of orthostatic hypotension is needed to prevent falls.
ýnother complex clinical problem involves the patient with bipolar disorder, Parkinson’s disease, and psychotic features. The very low incidence of EPS, combined with the benefit of both antipsychotic and antimanic efficacy, makes quetiapine a desirable option.23 Doses as low as 50 mg per day of quetiapine have been effective, while some patients have required 300 mg per day. Slow titration of quetiapine is recommended in the elderly: 25-50 mg per day every 3 days given in two divided doses.
Conclusion
Bipolar disorder is associated with an increased mortality rate across the lifespan, in part due to a higher rate of suicide. Other causes are noncompliance with treatment for comorbid medical conditions, and poor safety awareness that often leads to incidents and accidental injuries. Due to the chronic nature of the illness, 90% of patients have recurrent episodes and require ongoing maintenance therapy. An older patient with bipolar disorder who develops increasing medical problems may become less stable, less compliant with treatment, and prone to episodes of rapid cycling or mixed states of both manic and depressive features.3,4 Treatment compliance is a major issue, as the majority of patients will discontinue medications due to side effects, poor efficacy, or the desire to regain the energizing or activating feelings associated with mania and hypomania. Older adults often have more frequent episodes of mania and depression with a longer duration of symptoms than younger patients.4
The majority of patients with bipolar disorder achieve significant remission of symptoms with treatment, but 20-30% of these patients will display ongoing mood symptoms even with consistent compliance. This leads to disruption in the ability to work, maintain stable relationships, and attend to the needs of spouses and families.
Bipolar disorder in late life may manifest in a variety of ways, including mixed features of mania and depression, sustained irritability, and behavioral disturbances such as aggression. It is a complex disorder that requires ongoing treatment throughout the lifecycle.
The importance of psychosocial treatments and supports in bipolar disorder is often underemphasized. Older adults benefit greatly from psychosocial treatments, particularly those that focus on reducing stressful life events and maintaining a stable living environment.24 The social support provided through group treatment or family therapy is also of significant benefit to help cope with ongoing symptoms of the illness that may linger between episodes. Patients with bipolar disorder may have periods of unemployment, unstable relationships, and poor social functioning due to their illness.1-4 Older adults with bipolar disorder may have exhausted their resources, and may have minimal family support. Linkage to services for older adults offers significant chances for stability, and reduces the need for hospitalization. Caregivers of patients with bipolar disorder report significant levels of distress, with 93% feeling that their own health was impaired to a moderate degree.25
Information for patients and families is available through the Depression and Bipolar Support Alliance at: www.dbsalliance.org.
References
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