THE DOWNSIDE OF FEELING GOOD
| BIPOLAR DISORDER —Elliott Richelson, MD, Donald C. and Lucy Dayton Professor of Psychiatry and Pharmacology,
College of Medicine, Mayo Clinic, Rochester, MN; Consultant in Psychiatry, Pharmacology, and Neuroscience,
Mayo Clinic, Jacksonville, FL; and Distinguished Investigator, Mayo Foundation
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| Background: bipolar disorder (manic-depressive disorder) 2 poles of affect spectrum, ie, mania or hypomania and
depression; patients divided into bipolar type I (have had full-blown mania) and bipolar type II (have had lesser
forms of mania but many depressive episodes); prevalence—occurs in 1% to 2% of population with approximately
equal sex distribution; less common than unipolar depression (prevalence 5%-8%); high morbidity; can run in families
but no gene identified; 3.7% of adult Americans positive when screened for bipolar disorder, but 80% never
told; 30% untreated for >10 yr; some patients who initially present with unipolar depression eventually diagnosed
as bipolar (highly prone to suicide); leading cause of disability worldwide in individuals between ages 15 and 45 yr
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| Symptoms: depression—68% of patients in depressive phase; symptoms similar to unipolar depression, including
depressed mood, feelings of guilt or worthlessness, restlessness, sluggishness, fatigue, loss or gain of weight
or appetite, aches and pains, lack of interest, difficulty concentrating, change in sleep (frequent awakenings, especially
in early morning), suicidal thoughts, suicide attempts; mania—feelings of elation and ≥3 of following
symptoms, feelings of grandiosity, decreased need for sleep (usually indicates transition into manic phase), pressured
speech, flight of ideas, distractibility, increased activity (especially activities resulting in painful consequences,
eg, having affairs, overbuying), impaired functioning; may appear similar to schizophrenia but no
hallucinations or delusions
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Maintenance Treatment
| Mood stabilizers: goal to maintain stable mood; include lithium, anticonvulsants, atypical antipsychotic drugs; add
antidepressant if patient goes into depressive phase; fear that antidepressant will trigger manic episode or increase
frequency of manic switching
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| Lithium: mechanism— believed to inhibit interaction between receptors and G proteins; behaves like sodium or potassium
in kidneys; blood levels easily measured to determine when in therapeutic range; no known physiologic
role, but antimanic effects proven; adverse effects—long-term toxicity to kidneys, including kidney failure; produces
hypothyroidism in 10% to 12% of patients; rare cases of hyperthyroidism also possible; measure baseline
kidney and thyroid function before starting treatment, and repeat tests every 3 to 6 mo; other side effects include
mental dulling
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| Anticonvulsants: mechanisms—valproate and lamotrigine (Lamictal) work via sodium ion channels; gabapentin
works via calcium channels; divalproex (Depakote)—indicated for acute mania; data support use for maintenance;
may have efficacy for bipolar depression; lamotrigine—indicated for maintenance treatment of bipolar disorder and
may have efficacy in bipolar depression and acute mania; gabapentin—no convincing data on efficacy for mood
stabilization; Food and Drug Administration (FDA)—only lamotrigine approved for monotherapy and maintenance
of bipolar disorder, although data support use of carbamazepine (eg, Tegretol) and valproate
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| Atypical antipsychotic drugs: mechanism—serotonin and dopamine receptor antagonists or partial agonists; secondary
receptor effects (eg, blocking muscarinic acetylcholine receptors) relate to adverse effects; efficacy—all
FDA-approved for acute manic phase, appear efficacious for maintenance, may be promising as antidepressants in
bipolar patients; useful as first-line agents for augmenting divalproex or lithium
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Treatment of Bipolar Depression
| Antidepressants: used in combination with mood stabilizer; some data to show that mood stabilizer alone can treat
depression, but none FDA-approved for treating depressed phase of bipolar disorder; FDA-approved combination
drug— olanzapine and fluoxetine (Symbyax); data show better result than with single drug; quetiapine
(Seroquel)—also FDA-approved for depression in bipolar patients; supported by 8-wk placebo-controlled study
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Treatment of Acute Mania
| Anticonvulsants: divalproex and carbamazepine FDA-approved as monotherapy; lithium takes longer to work than
valproate; oxcarbazepine—some trials show efficacy but not FDA-approved; carbamazepine—infrequently used
because of induction of liver enzymes and blood dyscrasia
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| Atypical antipsychotic drugs: all FDA-approved for acute manic phase of bipolar illness; called atypical because
unlikely to cause extrapyramidal side effects seen with other antipsychotics; different propensities to cause weight
gain and other side effects
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| ANTIPSYCHOTIC DRUGS, OBESITY, AND THE METABOLIC SYNDROME —Dr. Richelson
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| Weight gain: caused by nearly all psychiatric drugs but seen more with olanzapine (Zyprexa) than with ziprasidone
(Geodon) or aripiprazole (Abilify); study data show—weight gain as shown by waist circumference reversibly increases
risk for diabetes in general population; severely mentally ill patients often obese to start with, but may gain
6 to 7 kg over 38 wk as side effect of drugs, and may not plateau after 1 yr; computed tomography (CT) shows
weight gain specifically intra-abdominal fat in schizophrenics compared to control group; intervene early by changing
drugs and diet and by increasing exercise; mechanism—probably antagonism of histamine H1 receptor; olanzapine
potent histamine H1 antagonist and appetite stimulant; also serotonin (5-hydroxytryptamine; 5-HT2C ) possibly
involved in appetite control; data show possible direct effect of antipsychotic drugs on beta cells in pancreas, as
well as effects in liver and muscle associated with inhibition of insulin release
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| Diabetes: in severely mentally ill—incidence 1.5 to 2 times higher than in general population, even before antipsychotic
use; family history of diabetes in 30% of schizophrenics, compared to 5% in general population; general
health risk—42% of schizophrenics obese, 75% smoke (may be self-treating cognitive deficits); drug-related risk–
obesity and increased atherogenic lipid profile associated with use of antipsychotic drugs; clozapine, olanzapine,
and risperidone can worsen or precipitate new-onset diabetes; FDA-imposed class warning label on all antipsychotics
for onset or worsening of diabetes; metabolic syndrome—waist circumference >40 in for men or >35 in for
women; hypertension; high triglycerides; low high-density lipoprotein (HDL); high fasting glucose; recommendation
for 150 min of exercise weekly; American Diabetes Association consensus group—found olanzapine and clozapine
associated with high risk for weight gain and worsening lipid profile; intermediate risk from risperidone and
quetiapine; least risk from ziprasidone and aripiprazole
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| Choice of antipsychotic drugs: consider—nature of psychiatric condition; target signs and symptoms to be
treated; past history of drug response; patient preference; need for special monitoring; also consider risk for obesity,
diabetes, and dyslipidemia; start with “metabolically friendly” drug—eg, aripiprazole, ziprasidone; however,
because of difficulty of treatment, efficacy most important criterion (stick with drug that works, even if not as metabolically
friendly; discuss risks with patient); hyperglycemia usually occurs over first 6 mo (monitor patients);
metabolic effects reversible, so if problems occur, switch to different drug; monitoring patients—obtain baseline
data on body mass index (BMI), waist circumference, blood pressure, fasting glucose and lipids, and family history
of diabetes; follow BMI every month, other parameters quarterly or yearly; consider referral to specialist; educate
patient and family
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| OTHER ISSUES IN PSYCHOPHARMACOLOGY —Andrea Wessell, PharmD, Assistant Professor of Pharmacy
and Clinical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston
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| New in antidepressant therapy: generic selective serotonin reuptake inhibitors (SSRIs) available over last few
years; citalopram, fluoxetine, and paroxetine on low-cost programs (eg “four dollar list”)
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| Choosing therapies: for treating depression, primary care physicians use consensus opinions or expert guidelines;
recent evidence base from National Institutes of Health (NIH) study called Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) good starting point in primary care setting
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| STAR*D trial: goals—determine efficacy of different antidepressants for patients failing initial therapy; evaluate
switching medication class vs augmentation with medication of same class; algorithm—citalopram (Celexa) first-
line therapy (relatively free of drug-drug interactions); nonresponders given choice of switching to cognitive therapy
or another drug; those who chose more drug therapy (level 2) randomized to— switching to another SSRI (sertraline
[Zoloft]), bupropion (eg, Wellbutrin), or venlafaxine (Effexor); or augmenting with bupropion, buspirone
(antianxiety agent); those who chose cognitive therapy—could augment it with venlafaxine or bupropion; level 2
nonresponders (level 3)—could switch (to nortriptyline or mirtazapine) or augment therapy (lithium or triiodothyronine
[T3]); level 3 nonresponders (level 4)—small number; switched to monoamine oxidase inhibitor (MAOI) tranylcypromine
(Parnate), or mirtazapine plus venlafaxine
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| STAR*D patients: adults who presented to psychiatric or primary care clinics; provider assessed depression; no recruitment
in magazines, newspapers, or other advertising; exclusion criteria included other psychiatric illnesses or
previous lack of response to antidepressants; method—open-label treatment but blinded assessment; primary end
point—remission of depression on basis of standardized scales at 12 wk and 1 yr; demographics—almost 2900
adults representing typical primary care population (≈20% black; large percentage of women); 75% had recurrent
depression, and >50% had family history of depression
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| STAR*D results: level 1—patients seen 5 times in 12 wk; treatment averaged 10 wk with citalopram; remission
rate 28%; time to remission, ≈ 6-wk; efficacy comparable in primary care and psychiatric clinics; no suicides, but
4% rate of severe adverse effects (intolerability, gastrointestinal effects); predictors of remission—white ethnicity;
female sex; employment; higher level of education; patients less likely to achieve remission—had longer index episodes,
other psychiatric illnesses, substance abuse, general medical disorders, lower baseline function; level 2
(switch arm)—727 patients randomized; remission rates similar, regardless of second drug choice; no safety or tolerability
differences; 4 patients hospitalized for suicidal ideation, no suicides; level 2 (augmentation arm)—565 patients;
remission rates similar between medication arms; tolerability better when bupropion added than when
buspirone added; level 2 (cognitive therapy arm)—182 patients attended up to 11 sessions; results similar for therapy
in primary care or psychiatric settings; efficacy similar to that of medication, but remission occurred 20 days
later; no side effects; level 3 (switch arm)— remission rate <20% for both drugs; level 3 (augmentation arm)—very
small remission rates, but too few patients to draw firm conclusions; level 4—very few remissions; MAOIs difficult
to tolerate
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| STAR*D conclusions: dose escalation and follow-up key; responders not on starting dose of citalopram at end of
level 1 (daily dose adjusted up to almost 40 mg); reevaluate and switch or augment if benefit minimal at 6 to 8 wk;
second-line relapse rates higher, but good options exist for second-line; 25% remission for medication switch, 30%
for augmentation; cognitive therapy as good as medication but takes longer
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| Switching antidepressants: goal—achieve remission and avoid discontinuation syndrome; switching among
SSRIs—stopping first drug and starting second one good, except for fluoxetine (long duration of action requires 1-
wk washout period, and new SSRI must be started at lower dose); switching from SSRI to venlafaxine—may stop
and start for all except paroxetine and fluoxetine (higher potential for drug-drug interactions); for these, taper required
(reduce dose by 25% every 4-6 wk); cross tapering— slowly decreasing first drug while increasing second;
recommended when drugs have different mechanisms; switching to or from MAOI—washout period (≥5 half-lives)
required for any drug
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| New information on onset of benefit with SSRIs: in past, antidepressants thought to take 4 to 6 wk before benefit
seen; recent 10 million-patient meta-analysis showed greatest absolute effects seen in first week
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| Paliperidone (Invega): newest atypical antipsychotic; active metabolite of risperidone; efficacy and safety similar
to others; claims may be made about improved social functioning, but no basis for this because new scale
used to show efficacy of palperidone (no comparison possible to older drugs); advantages include once-daily
dosing and slightly lower cost (but risperidone to go generic soon); counsel patients that they may see parts of
tablet in stool
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Suggested Reading
Cain RA: Navigating the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study: practical outcomes
and implications for depression treatment in primary care. Prim Care 34:505, 2007; Elias AN et al: Abnormalities
in glucose metabolism in patients with schizophrenia treated with atypical antipsychotic medications. Am J
Med 121:98, 2008; Jennex A, Gardner DM: Monitoring and management of metabolic risk factors in outpatients
taking antipsychotic drugs: a controlled study. Can J Psychiatry 53:34, 2008; Johannessen Landmark C: Antiepileptic
drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs
22:27, 2008; Gaynes BN et al: The STAR*D study: treating depression in the real world. Cleve Clin J Med 75:57,
2008; Gentil V: Introduction to bipolar disorder and comorbid conditions. J Clin Psychiatry: 69:e1, 2008; Ghaemi
SN: Treatment of rapid-cycling bipolar disorder: are antidepressants mood stabilizers? Am J Psychiatry 16:300, 2008;
Hirschfeld RM: Screening for bipolar disorder. Am J Manag Care 13(7Suppl):S164, 2007; Philip NS et al: Augmentation
of antidepressants with atypical antipsychotics: a review of the current literature. J Psychiatr Pract 14:34,
2008; Mantere O et al: Clinical predictors of unrecognized bipolar I and II disorders. Bipolar Disord 10:238, 2008;
Taylor MJ: Rapid onset of true antidepressant action. Curr Psychiatry Rep 9:475, 2007; Van Winkel R et al:
Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder. Bipolar Disord
10:342, 2008.
Educational Objectives
| The goal of this program is to increase primary care physicians’ ability to recognize and optimally treat patients with
psychiatric disorders. After hearing and assimilating this program, the participant will be better able to:
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 | 1. Recognize the phases of bipolar disorder.
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| 2. Describe the goals of treatment for the different phases of bipolar disorder.
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| 3. Evaluate the properties of anticonvulsants, antipsychotics, and antidepressants to prescribe the best treatment
for each phase of bipolar disorder.
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| 4. Recognize risks and avoid potentially serious side effects of obesity, metabolic syndrome, and diabetes among
patients on antipsychotic medications.
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| 5. Select sequential treatment options for patients with unipolar depression who fail to respond to first-line antidepressants.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of
the planning committee to disclose relevant financial relationships within the past 12 months that might create
any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity
promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr.
Richelson reported grant support from Janssen Pharmaceutica, and consulting arrangements with Janssen Pharmaceutica,
Somaxon, and Sarentis Therapeutics. Dr. Wessell and the planning committee reported nothing to
disclose.
Acknowledgements
Dr. Richelson’s lectures were recorded at 2007 Primary Care Update, held November 4-7, 2007, in Savannah, GA,
and sponsored by the Interstate Postgraduate Medical Association of North America. Dr. Wessell addressed An Intensive
Review of Family Medicine, held June 18-23, 2007, in Kiawah Island, SC, and sponsored by the Medical
University of South Carolina, Department of Family Medicine. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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