Tara Purvis, PharmD

Dr. Heiber is a clinical pharmacist, and Dr. Purvis is a psychiatry pharmacy resident, at Western Missouri Mental Health Center in Kansas City, Missouri.

, is characterized by recurrent fluctuations in mood, energy, and behavior, which impair global functioning.

 Genetics and environment influence this complex disorder that affects approximately 3.8% of the population.

 Clinical presentation varies widely; therefore, a complete history of symptoms is essential to diagnosis.

	Four illness episodes occur in BPD: mania, depression, hypomania, and mixed (simultaneous manic and depressive symptomatology).

 (bipolar I disorder) or hypomania (bipolar II disorder), which must occur only once for diagnosis. Mania is defined as persistently elevated, expansive, or irritable mood, lasting at least 1 week or requiring hospitalization. Onset is typically abrupt and symptoms escalate, lasting weeks to months. Symptoms include grandiosity, less need for sleep, pressured speech, flight of ideas, distractibility, risky behavior, and increased goal-directed activity. Hypomania is less severe, lasting for at least 4 days, without significant functional impairment.

	The majority of bipolar patients experience significant enduring depression throughout life.

 In fact, they will spend more time in either a depressed or euthymic state than in mania, hypomania, or mixed mood states. Up to 40% of patients experience mixed episodes, posing a treatment challenge, often requiring augmentation strategies.

 A paucity of research exists for bipolar depression, and those with a history of mixed episodes or rapid cycling (≥4 episodes/year) are often excluded from clinical trials, which limits evidence for treatment.

	Several published guidelines aid clinicians in treatment selection.

 Lithium, valproate, and carbamazepine are treatment options approved by the FDA for acute mania/mixed episodes associated with bipolar I disorder (see the online table at www.BipolarDisorders. com for details). Carbamazepine is not considered a first-line agent due to its hematologic safety concerns.

	Lamotrigine (Lamictal) is solely indicated for BPD maintenance treatment. To minimize the risk of Stevens- Johnson rash, one must titrate lamotrigine slowly (target dose 200 mg/ day), making it a poor candidate for acute treatment. Lamotrigine is thought to have a role in BPD depression; however, evidence remains limited.

	Continued therapy with a mood stabilizer remains the cornerstone for achievement and maintenance of remission. With monotherapy response rates as low as 30%, a single mood stabilizer is insufficient for many patients.

	The advent of second-generation antipsychotics (SGAs; eg, risperidone [Risperdal]) allowed for improved tolerability over first-generation antipsychotics (FGAs; eg, haloperidol [Haldol]). At typical dosages, SGAs cause fewer extrapyramidal side effects and less hyperprolactinemia than haloperidol and other FGAs. As few studies directly compare any SGA with traditional mood stabilizers, it cannot be said that any treatment is superior in treating BPD.

	Risperidone has proven efficacy in acute mania or mixed episodes in bipolar I disorder and can be given as monotherapy or in combination with lithium or valproate. The dosage range is 2 to 6 mg/day. Side effects include somnolence, anxiety, dizziness, and dose-dependent extrapyramidal symptoms. Though occurrence is rare, hyperprolactinemia is greatest with this SGA. Weight gain and metabolic issues may also occur.

	Olanzapine (Zyprexa) is indicated for the treatment of either acute or mixed mania episodes associated with bipolar I disorder and maintenance therapy. It can be prescribed as monotherapy or in combination with lithium or valproate. Frequent adverse reactions include weight gain, increases in cholesterol and other metabolic changes, as well as somnolence. The typical starting dose in BPD is 15 mg daily given at bedtime, with titration up to 20 mg as clinically indicated. Olanzapine combined with fluoxetine treats depressive episodes associated with BPD, notably with no reported increased risk of mania.

	Similarly, quetiapine (Seroquel) is indicated in acute manic episodes as either monotherapy or in combination with lithium or valproate. It is also approved for treating depressive episodes associated with BPD. Sedation, dry mouth, headache, and weight gain are frequent side effects associated with quetiapine. For depressive episodes, the target dose is 300 mg, whereas mania dosing may reach 800 mg daily.

	Ziprasidone (Geodon) is another option for patients with either acute mania or mixed episodes associated with BPD. Initial dosing for mania is 80 mg/day in divided doses, and can be rapidly titrated to 160 mg/day. Absorption is increased twofold when taken with at least 500 calories.

 Somnolence, headache, and dizziness are the most commonly reported adverse events. Though ziprasidone has received negative attention for prolongation of QTc, this rarely reaches clinical significance. Routine monitoring with electrocardiogram has not been proven worthwhile; however, it is recommended in patients with cardiovascular risk factors or those taking concurrent medications known to prolong QTc.

	Aripiprazole (Abilify) has indications for stabilization of acute manic or mixed episodes and maintenance therapy in BPD. It also has approval for use as a secondary agent when lithium or valproate monotherapy fails. The most commonly reported side effects for aripiprazole include headache, gastrointestinal complaints, somnolence, akathisia, agitation, and insomnia. BPD starting dose is 15 mg and can be titrated up to 30 mg daily.

	Paliperidone (Invega) has not yet been evaluated for BPD treatment. The risk for agranulocytosis with clozapine deterred much study for BPD, though it is occasionally used in refractory cases.

	• Fasting blood glucose/hemoglobin A1C

	Beyond using quetiapine or olanzapine/ fluoxetine treatment, some data support the use of an antidepressant if the person is receiving a mood stabilizer or antipsychotic. The risk for switching to a manic episode has been reported to be as high as 40%.

 Potential correlates of this risk include signs of a mixed depression such as motor activation, pressured speech, or racing thoughts prior to treatment with the antidepressant. 

	As a lifelong fluctuating illness, people with BPD often require continued medication treatment. Upon achieving remission, dosage(s) may be lowered if desired; however, the 5-year relapse rate is 73% even with continued medication therapy.

	Pharmacists play an essential role in optimizing treatment for a patient with BPD. Obtaining accurate medication histories is a priority with this population, helping to guide treatment selection or identify an underlying cause (eg, antidepressant use). Other valuable roles of the pharmacist include recommending appropriate dosing strategies, implementing pertinent monitoring parameters, evaluating signs and symptoms of toxicity, and increasing awareness of potential drug interactions.

	Educating the patient is of utmost importance in those with BPD. Helping patients become aware of early symptoms of mania as well as depression can help them seek assistance before becoming severely ill. Providing the patient with the knowledge to prevent or treat potential side effects improves adherence to medication therapy. %u25A0

Articles

The Many Faces of Bipolar Disorder

Dr. Hieber is a clinical pharmacist at Western Missouri Mental Health Center in Kansas City, Missouri. Dr. Purvis is a psychiatry pharmacy resident at Western Missouri Mental Health Center. 

Though previously thought to be a childhood disorder, attention-deficit/hyperactivity disorder (ADHD) is now known to persist into adulthood.

 "Growing out" of ADHD is unlikely; rather, one may learn to compensate for the impairment. Hyperactive symptoms may subside in adulthood, with inattentive symptoms becoming more prevalent. In both children and adults, ADHD can negatively affect socialization, school or occupational work, and relationships.

Affecting 8.7% of children and 4.4% of adults, ADHD is hereditary.

Several genes related to transmission of the neurotransmitter dopamine, and to a lesser extent, norepinephrine and serotonin, are implicated in ADHD.

 These neurotransmitters are associated with the brain's arousal network, which can be stimulated inappropriately in one who has ADHD. Other risk factors found in ADHD include prenatal exposure to tobacco or alcohol, low birth weight, and perinatal complications.

Diagnostic and Statistical Manual of Mental Disorders, 

an individual with ADHD displays developmentally inappropriate levels of inattention, hyperactivity, and impulsivity persisting for at least 6 months.

Presentation ranges from difficulty organizing tasks and forgetfulness in daily activities to excessive talking and interrupting others. Symptoms must begin in childhood, be present in 2 or more settings, and cause marked impairment in functioning. Despite this impairment, a number of effective treatment options exist for people with ADHD.

Up to 80% of individuals with ADHD respond to stimulants; therefore, these agents are first-line options for both children and adults.

 By enhancing the neurotransmission of dopamine and norepinephrine, stimulants have the greatest effect on social and classroom behaviors.

The benefit of stimulants will often appear within days of achieving an adequate dose.

Evidence-based reviews conclude that all stimulant medications are equally effective, though an individual may respond to one stimulant over another.

 Stimulants are available in short-acting, intermediate-acting, and long-acting formulations.

 Short-acting and intermediate-acting medications' peak effect occurs 1 to 3 hours after administration, necessitating the need for multiple daily dosing. School-age children may benefit from long-acting agents that eliminate the need for midday dosing. Depending on the formulation of the medication, ease of administration may be increased by crushing short-acting or intermediate-acting agents, or sprinkling the contents of a long-acting capsule over food.

Over the past decade, the advancement of new formulations has led to an increase in the use of long-acting agents. Examples include an osmotically controlled-release drug delivery system (methylphenidate HCl, Concerta), transdermal methylphenidate patch (methylphenidate transdermal system, Daytrana), and a conjugated 

-amphetamine molecule (lisdexamfetamine dimesylate capsules, Vyvanse). Along with simplifying dosage regimens, these options were developed to decrease diversion and abuse of the medications.

Guidelines suggest initiation with a low dose to minimize side effects and achieve the lowest effective dose.

 Decreased appetite, sleep and gastrointestinal disturbances, irritability, headache, tachycardia, and jitteriness

are common, but often transient side effects. Although reported clinically, growth suppression was not reported consistently in clinical trials.

Stimulants may cause a minimal increase in heart rate and blood pressure (dose-related); experts recommend that those treated with stimulants are monitored at baseline and periodically throughout treatment, especially children with underlying cardiac abnormalities or arrhythmias.

 Whereas studies have not shown an association between stimulants and changes in electrocardiograms, monitoring is recommended in high-risk patients. Medications used to treat ADHD contain an FDA warning about the possible cardiovascular risks and psychiatric adverse events,

 along with a manufacturer's warning indicating the potential for abuse.

Atomoxetine (Strattera) is the only FDA-approved nonstimulant medication used as a major second-line, and in some cases first-line treatment for ADHD (those with a history or concern of substance abuse).

 The drug is a selective norepinephrine reuptake inhibitor and has a slower onset of action than stimulants. It may take 2 to 4 weeks to determine clinical effectiveness. Side effects are similar to stimulants; however, an increase in sedation and sexual disturbances have been reported. Suicidal ideation and hepatotoxicity have been reported in the literature, and this risk is included in the manufacturer's warning label.

Second-line treatment options should be considered for patients who have failed 2 to 3 stimulant medications. Along with atomoxetine, antidepressants (eg, venlafaxine, bupropion, tricyclic antidepressants) are second- or third-line agents.

 These have shown only modest efficacy for the treatment of ADHD, but may be beneficial for patients with comorbid depression or substance abuse.

Several studies have indicated that modafinil, approved for treating narcolepsy, has shown improvement in ADHD.

 Concerns of Stevens-Johnson syndrome led an FDA advisory committee to recommend against approval of modafinil for the treatment of ADHD in children. Clonidine and guanfacine, a

-adrenergic agonists, may be adjunctive treatment options in children with ADHD, especially those experiencing sleep disturbances.

Behavioral interventions were not more effective than medication, according to recent evidence.

 Pharmacists can play a major role in educating patients and caregivers.

1. Heath CT Jr, Wright HH, Batey SR. Attention deficit hyperactivity disorder: does it affect adults too? 

2. Froehlich TE, Lanphear BP, Epstein JN, Barbaresi WJ, Katusic SK, Kahn, RS. Prevalence, recognition, and treatment of attention deficit/hyperactivity disorder in a national sample of US children. 

3. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. 

4. Faraone SV, Khan SA. Candidate gene studies of attention-deficit/hyperactivity disorder. 

5. Banerjee TD, Middleton F, Faraone SV. Environmental risk factors for attention-deficit hyperactivity disorder. 

Diagnostic and Statistical Manual of Mental Disorders

. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.

7. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD.

8. McMaster University Evidence-Based Practice Center. Treatment of Attention-Deficit Hyperactivity Disorder. Ottawa, Canada: Canadian Coordinating Office for Health Technology Assessment; 1998.

9. Brown RT, Amler RW, Freeman WS, et al. Treatment of attention-deficit/hyperactivity disorder: overview of the evidence. 

10. Findling RL. Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review. 

11. Rappley MD. Attention deficit-hyperactivity disorder. 

12. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameters for the use of stimulant medications in the treatment of children, adolescents, and adults

13. Spencer T, Biederman J, Wilens T. Growth deficits in children with attention deficit hyperactivity disorder. 

14. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. 

15. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. 

16. FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events. Food and Drug Administration Web site. www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html. Accessed December 12, 2008.

17. Asherson P. Clinical assessment and treatment of attention deficit hyperactivity disorder in adults. 

18. Newcorn JH, Kratochvil CJ, Allen AJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. 

19. Abboud L. Lilly warns doctors about Strattera. 

20. Edmund H. A comparative analysis of antidepressants and stimulants for the treatment of adults with attention-deficit hyperactivity disorder. 

21. Wilens TE, Spencer TJ, Biederman J. A review of the pharmacotherapy of adults with attention-deficity/hyperactivity disorder. 

22. Conners CK, Casat CD, Gualtieri TC, et al. Bupropion hydrochloride in attention deficit disorder with hyperactivity. 

Approved and investigational uses of modafinil: an evidence-based review. 

24. Conner DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention deficit hyperactivity disorder. 

25. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. 

26. Wolraich ML, Wibbelsman CJ, Brown, TE, et al. Attention-deficit/hyperactivity disorder among adolescents: a review of the diagnosis, treatment, and clinical implications. 

27. American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. 

28. Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and use. 

Let's Focus on ADHD

Dr. Purvis is a psychiatric pharmacyresident and Dr. Hieber is a clinicalpharmacist at Western Missouri MentalHealth Center in Kansas City.

Fifty years ago, the terms "everyman'spsychosis" and "reversiblemadness" referred to a mentaldisorder to which everyone is susceptible&#8212;delirium, an acute confused stateoften overlooked by physicians.

Up to 40% of hospitalized elderly patientsexperience delirium, one of themost preventable hospital-acquiredadverse events.

 Failure to uncover theunderlying etiology of delirium resultsin extended stays, increased costs, andincreased morbidity and mortality.

Delirium commences abruptly and encompassesa broad range of disturbances.These range from hyperactive tohypoactive states, with fluctuations inlevel of consciousness, attention, cognition(memory impairment, disorientation,language disturbance), and perception(visual/tactile hallucinations).Symptoms, including sleep pattern disturbanceand psychomotor behavior,vary throughout the day and generallyresolve within 10 to 12 days.

The primary goal in management is toidentify the underlying etiology and initiateimmediate interventions to ensurepatient safety. In elderly patients, deliriumis commonly a result of acute illnessor medication, the latter being themost common reversible cause.

 Halfof all cases are missed by physicians;thus, pharmacists play a major roleby recommending alternative treatmentstrategies and minimizing the use ofhigh-risk medications (eg, anticholinergics,analgesics).

 forpotential causes and treatment suggestions.Table 2 provides tips the pharmacistcan implement to help prevent ortreat delirium.

Delirium Causes and Treatment Recommendations

Optimize environmental cues for day/night, nonpharmacotherapy options for insomnia

Provide familiar objects, moderate amount of stimuli, educate staff

Discontinue medication(s) or lower dose; recommend alternative with less deliriogenic risk

Studies examining pharmacologicprevention investigated low-dose antipsychotichaloperidol, anticonvulsantgabapentin,and an acetylcholinesteraseinhibitor (ACI), donepezil.

 No trialwas overwhelmingly significant; therefore,using medication to prevent deliriumis not currently recommended.

Acute agitation with delirium maynecessitate short-term pharmacologictreatment; however, if the cause ofdelirium is addressed, further interventionmay not be necessary. Standardpractice involves use of first-generationantipsychotics (primarily haloperidol).

 Using lower doses of haloperidol,between 0.5 and 4.5 mg/day,keeps extrapyramidal side effects toa minimum. The evidence for use ofsecond-generation antipsychotics (eg,risperidone, olanzapine, quetiapine, ziprasidone)is expanding.

A recent analysis of haloperidol versusrisperidone, olanzapine, and quetiapinedetermined that all agents havesimilar efficacy in treatment of agitationin delirium.

 Second-generation anti-psychotics, especially olanzapine and quetiapine, are sedating,which may be beneficial in some situations. Choosing anagent should involve evaluating side effect profiles of eachpotential medication.

Current controversy exists regarding evidence that mortalityis increased in elderly patients receiving antipsychotics.

Clinical significance of these findings is under debate.

If applicable, recommend alternative therapy

Obtain blood levels when appropriate (eg, lithium, phenytoin)

Adjust dosages in renal or hepatic impairment

Actively participate in medication reconciliation

Up to 40% of hospitalized elderly patients experience delirium, a highly preventable condition. Pharmacists play an important role by recognizing the signs and monitoring and reconciling medications.