Use of Neuroleptics in Primary Care for the Management of Bipolar Disorder

by Michael Menaster, MD

Summary of the State of Affairs

Primary care physicians face several challenges in managing patients with bipolar disorder.  While primary care physicians frequently treat patients with serious psychiatric disorders, it is a challenge for them to keep current with advances in psychopharmacology.  This article is intended to help primary care physicians in this regard. 

Another challenge involves bipolar disorder’s complex, chronic nature.  More common than previously thought, BSDs may affect up to 30% of primary care patients presenting with anxiety or depressive symptoms (Piver, 2002).  Primary care physicians failed to diagnose or misdiagnosed BSD among 78% of patients who screened positive for BSD (Frye, 2005).  Several factors explain this challenge.  Bipolar disorder may present in several ways, including depressive, hypomanic, or manic episodes (therefore, the term bipolar spectrum disorders (BSDs) better characterizes this syndrome).  These diverse presentations contribute to the difficulty that primary care physicians face in making the correct diagnosis.  In addition, approximately 80% of BSD patients present with depressive episodes, which also last three times longer than manic episodes.  Primary care physicians therefore tend to misdiagnose BSD patients with unipolar depressions.  In addition, primary care physicians frequently fail to detect hypomania, a defining feature of bipolar II disorder.  Further complicating the diagnosis of BSDs are co-morbid conditions, particularly anxiety disorders, substance abuse, and personality disorders, which may disguise BSDs.

For patients, the consequences of failing to diagnose BSDs include loss of employment, excessive use of health care resources, disturbed interpersonal relationships, and impaired quality of life.  Indeed, in comparison to major depression and schizophrenia, BSDs have equally high or even higher levels of impairments and disabilities (Pini, 2005).  The total societal cost for BSD is estimated to be $45 billion annually (Sajatovic, 2005).

For all of these reasons, primary care physicians should have a practical knowledge of the acute and chronic management of bipolar disorder.  In particular, they should be familiar with treatment alternatives, common side effects, and potential drug-drug interactions that may occur with BSD medications.

 Improving Diagnostic Accuracy of BSDs

Ways of to diagnose BSD more accurately include the use of screening instruments, semi-structured interviews, and collateral history.  Screening instruments offer several advantages.  These instruments are standardized, well validated, easily administered and scored, and provide a baseline to measure treatment progress.  Indeed, screening for BSD in psychiatric patients may improve the diagnostic accuracy of BSDs and may facilitate appropriate treatment (Hirschfeld, 2005).  For BSDs, the most common screening instrument is the Mood Disorder Questionnaire (MDQ), a 13-item, yes-no test, that most patients can easily complete on their own within five minutes (Hirschfeld, 2000).  MDQ scores of seven or greater are associated with higher rates of psychiatric admissions, emergency room visits, and outpatient visits to primary care physicians.  Its sensitivity and specificity for detecting BSDs are 0.58 and 0.93, respectively; this means that while the MDQ may rule out BSDs, it does not effectively rule it in.  In other words, primary care physicians should not diagnose BSDs solely based upon the results of the MDQ.  Instead, they should base their diagnosis upon a comprehensive history, mental status examination, and, when available, collateral history.

The MDQ is available at no cost via

Treatment Goals for BSDs

Depending upon the severity of the BSD, particularly the presence of the patient being a danger to him/herself or others, or unable to provide for basic necessities of life, the patient may require hospitalization, day treatment, or intensive outpatient facility.  When in doubt, obtain a psychiatric consultation and err on the side of patient safety.

Immediate treatment goals include informed consent (when possible), baseline laboratories, and rapid mood stabilization.  Long-term treatment goals involve close follow-up, medication compliance, treatment of any co-morbid psychiatric conditions, and management of any side effects.

Instead of being merely a written legal document, informed consent should be an ongoing and interactive process between the primary care physician and patient.  It should include a discussion BSD’s nature, proposed treatment, side effects and risks, treatment alternatives, and prognosis without treatment.  This process can bring forth any patient medication preferences and unrealistic expectations such as a “cure.”  The Internet, direct-to-consumer advertising, and significant others’ anecdotal experiences are some common sources of unrealistic expectations (Menaster 2002).

Commonly used BSD medications include lithium, divalproex, carbamazepine, oxcarbamazepine, topiramate, and second-generation antipsychotics.  While lithium and divalproex have traditionally been the treatments of choice for BSDs, patients with BSDs frequently become non-compliant or require adjunctive therapy when taking these medications.

Known as second generation antipsychotics, the atypical antipsychotics, risperidone, olanzapine, and quetiapine, have the FDA’s approval to treat acute manic episodes associated with BSDs.  Most atypical antipsychotics are efficacious in acute manic episodes, while some are effective in BSD depression and in BSD maintenance treatment.  Specifically, olanzapine, risperidone, and quetiapine are effective in treating manic episodes as either as monotherapy or in combination with mood stabilizers, such as lithium and divalproex.  In addition, the significantly low rates of extrapyramidal side effects are making atypical antipsychotics the treatment of choice of acute manic episodes.  Because weight gain dyslipidemias, and hyperglycemia are potential side effects of antipsychotics, baseline BMI, lipid panel, and fasting blood glucose should be obtained.  Although second-generation antipsychotics do not appear to cause tardive dyskinesia (TD), evaluation of patients at baseline and follow up for movement disorders is warranted.

For BSD depression, antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or bupropion, are not recommended as monotherapy; antidepressants put BSD patients at risk for switching into manic episodes.  However, atypical antipsychotics, such as olanzapine and quetiapine, offer antidepressant activity without destabilizing mood.  These antipsychotics may improve mood by dowregulating serotonin 5-HT(2A) receptors, while their concomitant dopamine D(2) antagonism protects against mood destabilization (Yatham, 2005).

Several studies support the efficacy of atypical antipsychotics in manic episodes.  An international, double blind, placebo controlled study compared lithium to quetiapine monotherapy in treating BSD manic episodes.  Quetiapine compared favorably to lithium, was well tolerated, and resulted in significant improvement by day 7 and continued to increase thereafter (Bowden, 2005).  Another study compared quetiapine monotherapy to divalproex in 50 adolescents with BSD presenting with manic episodes.  This study found that 400-600 mg daily of quetiapine had a more rapid onset of action and a greater remission rate (DelBello, 2006).

An 88-week study in adolescent BSD found that quetiapine was efficacious and well tolerated, without extrapyramidal symptoms (EPS) or tardive dyskinesia (McConville, 2003).  A retrospective chart review for BSD outpatients who had been prescribed adjunctive quetiapine found that, for the entire sample, low-dose quetiapine augmentation significantly improved clinician-rated bipolar severity scores for mania, depression, and overall bipolar illness.  Specifically, quetiapine reduced insomnia, agitation, irritability, and mood disturbance.  Its side effects were mild and transient with sedation and dizziness being most common.  The study concluded that low-dose quetiapine may be a useful and well-tolerated adjunct for some bipolar patients with incomplete response to lithium or valproate (Sokolski, 2003).

Quetiapine is a cost-effective treatment for BSDs.  One study found an inverse correlation between initial quetiapine dose and subsequent mental health costs.  Specifically, for each milligram of quetiapine prescribed initially, subsequent mental health costs fell by $1.31.  The study concluded that higher initial doses of quetiapine may be more effective in stabilizing BSD patients (Gianfrancesco, 2005a).  Another study compared comparing quetiapine, risperidone and olanzapine, and found non-pharmaceutical health care costs associated with quetiapine were lower.  Based on prescription charges, olanzapine appeared more costly at an equivalent daily dose than risperidone or quetiapine (Gianfresco, 2005b).  These studies support the use of brand-name antipsychotics which can reduce overall treatment costs.

Reasons for Reluctance to Prescribe Atypical Antipsychotics in BSDs

Despite these positive results, primary care physicians may still be reluctant to prescribe neuroleptics, also known as antipsychotics or major tranquilizers.  Traditional neuroleptics, such as haloperidol and chlorpromazine, are called conventional or first-generation antipsychotics, while newer neuroleptics, such as quetiapine, risperidone, and aripiprazole, are called second-generation or atypical antipsychotics.  The term “atypical antipsychotics” sounds intimidating for a patient considering this treatment.  However, “atypical” merely refers to the fact that these antipsychotics affect both serotonin and dopamine receptors.  Understandably, patients and even some primary care physicians may associate these medications as used only for “crazy” people.  Side effects, such as weight gain, EPS, tardive dyskinesia, and hyperglycemia also contribute to hesitancy in their use.

However, the atypical agents may cause side effects, such as EPS and weight gain, particularly with long-term use.  However, studies found EPS rates associated with atypical antipsychotics as being relatively uncommon, in the 0-15% range.  For example, a randomized, double blind, placebo-controlled study of 302 patients with BSD manic episode found that flexibly dosed quetiapine (up to 800 mg/day), haloperidol, and placebo had sedation as the only common side effect (12.7%).  EPS, including akathisia, was actually less with quetiapine as compared to placebo (12.7% vs. 15.8%, respectively) (McIntyre, 2005).

Challenges in Treating BSDs

A major challenge in treating BSDs is denial, a common response to any illness.  In BSD, denial is common and contributes to treatment non-compliance.  Patient education, which is an element of informed consent, and family interventions can reduce denial.  Reminding the patient of the previous depressive and manic episodes may be useful.

Dealing with angry BSD patients is another challenge for primary care physicians.  It is common for patients with BSD to be angry.  While sometimes this anger is unreasonable, frequently it arises from with unmet expectations.  This anger can impact the physician-patient relationship and medication compliance.  It is important to understand the nature of the patient’s anger, not take it personally, and help the patient find constructive ways of dealing with anger (Menaster, 2004).

Another challenge is managing co-morbid psychiatric conditions.  As mentioned above, anxiety disorders are the most commonly co-occurring psychiatric syndromes with BSDs.  Studies show that some BSD medications may treat certain anxiety disorders.  Valproate can treat panic disorder efficaciously.  Lamotrigine, risperidone, and olanzapine are effective in posttraumatic stress disorder.  The atypical antipsychotics, risperidone, olanzapine, and quetiapine are efficacious adjuncts in treatment-resistant obsessive-compulsive disorder (OCD).  Risperidone, olanzapine, and quetiapine are effective treatments for panic disorder.  As described above, these mediations affect serotonin receptors, which may explain their anxiolytic effects.  In particular, one case report found low dose quetiapine (50 mg daily) rapidly effective in treating agoraphobia and OCD in a patient with BSD (Menaster, 2005).

Still another challenge is managing medication side effects.  Every medication, including placebo, has the potential to cause side effects.  Possible side effects of atypical antipsychotics include EPS, TD, weight gain, sedation, and sexual dysfunction.  Using the lowest effective dose is one way to minimize these side effects.  The choice of medication is another to reduce the frequency of these side effects.  Second-generation antipsychotics have lower rates of EPS and TD as compared to conventional antipsychotics.  Clozapine, olanzapine, and risperidone are associated with the greatest degree of weight gain (Sussman, 2003).  In contrast, long-term treatment with quetiapine was associated with minimal weight gain.  For patients who gain weight during antipsychotic treatment, topiramate can control weight gain without exacerbating psychosis (Lin, 2005).  Other interventions include metformin, food diaries, exercise, and dietician consults.  However, stimulants such as amphetamines, are contraindicated due to the risk of psychosis.  In addition, quetiapine does not increase the risk of developing type II diabetes (Sussman, 2003).


Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005 Jan;66(1):111-21

DelBello MP, Kowatch RA, Adler CM, et al. A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry 2006 Mar;45(3):305-13

Frye MA, Calabrese JR, Reed ML, et al. Use of health care services among persons who screen positive for bipolar disorder. Psychiatr Serv 2005 Dec;56(12):1529-33

Gianfrancesco F, Pesa J, Wang RH, Comparison of mental health resources used by patients with bipolar disorder treated with risperidone, olanzapine, or quetiapine.J Manag Care Pharm 2005 Apr;11(3):220-30

Gianfrancesco F, Wang RH, Pesa J. Relationship between initial quetiapine dose and effectiveness as reflected in subsequent mental health service use among patients with schizophrenia or bipolar disorder. Value Health. 2005 Jul-Aug;8(4):471-8

Hirschfeld RM, Cass AR, Holt DC, et al. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract 2005. Jul-Aug;18(4):233-9

Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and Validation of a Screening Instrument for Bipolar Spectrum Disorder: the Mood Disorder Questionnaire. Am J Psychiatry, 2000: 157 (11) 1873-1875.

Lin YH, Liu CY, Hsaio MC. Management of atypical antipsychotic-induced weight gain in schizophrenic patients with topiramate. Psychiatry Clin Neurosci 2005. Oct;59(5):613-5

McConville B, Carrero L, Sweitzer D. Long-term safety, tolerability, and clinical efficacy of quetiapine in adolescents: an open-label extension trial. J Child Adolesc Psychopharmacol, 2003 Spring;13(1):75-82

McIntyre RS, Becher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005 Oct;15(5):573-85

Menaster MJ. Effects of Quetiapine in Panic Disorder with Agoraphobia and Obsessive-Compulsive Disorder in a Patient with Bipolar Disorder, Psychiatry 2005, 2005, Sept. 2(9):17-18

Menaster M. Role of Unmet Expectations, Clin Psychiatry News, 2004. Mar 32(3):14

Menaster M, When ‘informed’ patients think they know what treatment is best. Current Psychiatry. 2002 Aug;1(8):25

Pini S, de Queiroz V, Pagnin D, Pezawas L, et al. Prevalence and burden of bipolar disorders in European countries. Eur Neuropsychopharmacol. 2005 Aug;15(4):425-34

Piver A, Yatham LN, Lam RW. Bipolar spectrum disorders: new perspectives. Can Fam Physician 2002 Jul;48:1190

Sajatovic M. Bipolar disorder: disease burden. Am J Manag Care 2005 Jun;11(3 Suppl):S80-4

Sokolski KN, Denson TF. Adjunctive quetiapine in bipolar patients partially responsive to lithium or valproate. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):863-6

Sussman N. The implications of weight changes with antipsychotic treatment. J Clin Psychopharmacol. 2003 Jun;23(3 Suppl 1):S21-6

Yatham LN, Goldstein JM, Vieta E. Atypical antipsychotics in bipolar depression: potential mechanisms of action. J Clin Psychiatry. 2005;66 Suppl 5:40-8