ATYPICAL BIPOLAR DISORDER/EATING DISORDERS
From 2006 Behavioral Health Symposium, presented by Kaiser Permanente Southern California
| STRATEGIES IN MANAGING THE ATYPICAL BIPOLAR PATIENT —Michael J. Gitlin, MD, Professor of Psychiatry,
the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), and Director, Adult Psychiatry,
Outpatient Mood Disorders Program, UCLA Medical Center, Neuropsychiatric Institute
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| Other anticonvulsants in bipolar disorder: include phenytoin (Dilantin), oxcarbazepine (Trileptal), levetiracetam
(Keppra), zonisamide (Zonegran), topiramate (Topamax), gabapentin (Neurontin), and tiagabine (Gabitril); phenytoin—
2 double-blind studies found 300 mg more effective than placebo as add-on treatment in acute mania and in maintenance
therapy; oxcarbazepine—probably more effective than studies suggest (studies not well done); studied in 7 patients in
early double-blind placebo-controlled trial; 3 other small double-blind studies compared it to lithium, haloperidol, and
valproate; no more studies likely to emerge (soon off-patent); similar to carbamazepine (eg, Tegretol), but with fewer
side effects (except for hyponatremia); not associated with blood dyscrasias, fewer drug–drug interactions, and no monitoring
of complete blood cell count (CBC) required; levetiracetam—shown efficacious in open studies (no controlled
studies); zonisamide—3 open studies, but no controlled studies; largest study involved 62 outpatients; some indication of
efficacy; related to topiramate and associated with weight loss; topiramate—positive reports in open trials, but 5 negative
double-blind placebo-controlled studies in acute mania (unpublished data); double-blind placebo-controlled study in
adolescents looking at effect on mania stopped after negative results surfaced; large case series indicates possibility of
use of topiramate as maintenance therapy (despite lack of efficacy in acute mania); side effects include weight loss;
gabapentin—2 double-blind studies showed gabapentin associated with negative results in patients with acute mania/hypomania
(placebo more effective in one study; mean daily dose of 3941 mg deemed ineffective, compared to placebo in
second study); consider use in anxious bipolar patients; tiagabine—3 open studies involving 47 patients with bipolar
disorder; no significant efficacy seen using daily doses ranging from 1 to 40 mg; new-onset seizures occurred in 4 patients;
use with caution (speaker suggests writing note in chart regarding risk)
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 | Bipolar disorder type I: polypharmacy the rule, not exception; according to data from 1995, <20% of patients on one
medication, and one-third of patients on ≥4 medications; in 2004, Stanley database showed average patient on 4
medications over 12-mo period; can combine any mood stabilizer with any other mood stabilizer, but use caution
when combining carbamazepine with clozapine because of effect on bone marrow
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| Bipolar disorder type II: acute mania—database of patients on either lithium or valproic acid (eg, Depakote) and antipsychotic
or placebo added using double-blind methodology (testing additive efficacy of second-generation antipsychotic
agent); multiple studies with risperiodone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) show
typical drug-placebo difference in response rates 20% to 25%; currently, mood stabilizer plus second-generation antipsychotic
agent treatment of choice for patients with acute mania; maintenance—National Institute of Mental Health
(NIMH) study showed combination therapy more effective than lithium or carbamazepine therapy alone in reducing
number of manic episodes, especially in patients who exhibit rapid cycling; another small study found lithium plus valproic
acid more effective than lithium alone, but combination therapy associated with greater side effect burden; study
looking at lithium or valproic acid with olanzapine, compared to lithium or valproic acid alone, found addition of olanzapine
slightly improved time to recurrence of mania or depression (dropout rate 86%)
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| Thyroid augmentation: used in patients who fail maintenance therapy (eg, patients who cycle rapidly or who continue
to relapse); goal of treatment to cause florid hyperthyroidism in these patients with high doses of levothyroxine (eg, Synthroid;
0.3-0.5 mg); study looking at 11 patients with bipolar disorder types I and II given 0.15 to 0.4 mg levothyroxine
daily; results showed decrease in number and amplitude of manic and depressive episodes; another study involving 29
patients given levothyroxine ≤500 µg/day (≈5 times average replacement dose); results after 2- to 4-yr follow-up showed
marked decrease in number of manic episodes and hospitalizations; side effects minimal, ie, sweating and tachycardia;
bone density of long-term concern, especially in postmenopausal women
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| Clozapine: works well for treatment-resistant bipolar disorder; associated with risk for agranulocytosis, congestive cardiomyopathy,
pancreatitis, and weight gain; requires complete blood cell count (CBC) weekly; many large-scale open studies;
avoid combining clozapine with carbamazepine; study involving 38 patients with treatment-resistant bipolar disorder
randomly assigned to treatment as usual or usual treatment plus clozapine; moderate improvement seen with usual treatment
plus clozapine
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| Electroconvulsive therapy (ECT) for acute mania: difficulty obtaining informed consent; data suggest efficacy
equivalent whether treating acute mania or depression; open studies indicate high response rate; same number of treatments
as for depression; bilateral ECT possibly more effective than unilateral; insufficient data on ECT as maintenance
therapy
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| Omega-3 fatty acids (eicosapentaenoic acid; EPA): small double-blind placebo-controlled study in patients with
bipolar disorder types I and II; patients took 9.6 g daily (extremely large dose); patients taking omega-3 fatty acids described
fewer depressive symptoms than patients taking placebo; multicenter study involving 121 patients taking 6 g
EPA (vs DHA [docosahexaenoic acid]) for bipolar disorder or for rapid-cycling; no effect seen in either subgroup; another
double-blind placebo-controlled study looking at 75 patients randomized to adjunctive EPA or placebo; patients
taking EPA did somewhat better
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| Calcium channel blockers: verapamil—not likely effective in treating bipolar disorder; capacity to cross blood-brain
barrier unclear; nimodipine (Nimotop)—used in patients with subarachnoid hemorrhage; stabilizes membranes through
calcium channel; 2 small double-blind studies with “intriguing” results; expensive despite availability of generic; subgroups
of calcium channel blockers may be shown effective in future, but, presently, literature does not support their use
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| Psychosocial adjunctive therapies: most impressive database (large well-controlled sophisticated studies); family-
focused treatment (FFT)—principles and techniques adapted from schizophrenia literature (behavioral family management);
basic principles are assessment, psychoeducation (including “relapse drill”), training in communication enhancement,
and problem-solving skills; study shows patients treated with medication and FFT had significantly reduced
relapse rates, with fewer depressive episodes, than patients treated with medication alone; effect greatest in patients with
“high expressed emotion” families; effect not based on compliance with medication therapy; same study at 2-yr follow-
up showed same treatment effect, better medication adherence, and fewer hospitalizations in patients engaged in FFT;
cognitive therapy—dramatic difference seen in patients receiving 12 to 18 sessions of cognitive therapy plus 2 “booster”
sessions; effect seen in mania, depression, hospitalizations, and number of days ill; increased compliance; group
psychoeducation—120 patients with bipolar disease in remission randomly assigned to treatment as usual plus psychoeducation
or unstructured group meetings; lower relapse rates and fewer hospitalizations in patients receiving psychoeducation;
interpersonal and social rhythm therapy (IPSRT)—focuses on sleep-wake cycles, education, and coping
strategies; data reasonably good, but include flawed study that compared IPSRT to intensive clinical management (considered
control group, ie, placebo group, but speaker considers this misnomer since actually effective treatment); cognitive-behavioral
therapy (CBT)—methodologic issues associated with negative study included 15% of patients not taking
mood stabilizers, CBT started in patients in acute phase, and patients with greater number of episodes did worse with
CBT
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| GENERAL TREATMENT PRINCIPLES OF EATING DISORDERS —Scott B. Richards, MD, Department of Psychiatry
and Addiction Medicine, Southern California Permanente Medical Group, Vista, CA
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| Anorexia nervosa (AN): Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria—
refusal to maintain body weight at ≥85% of expected weight for age or sex; intense fear of gaining weight or becoming
fat; perceptual disturbance in how one’s body weight experienced; in postmenarcheal females, amenorrhea for ≥3 consecutive
months; label as eating disorder not otherwise specified (EDNOS) if patient meets first 3 criteria, but still menstruating;
restricting subtype—patient uses food restriction for weight loss; binge-purge subtype—50% to 75% of
patients with AN also have bulimia nervosa (BN); 80% to 85% of patients engage in restrictive eating before onset of
BN; even after treatment for BN, some patients return to restricting food intake
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| Bulimia nervosa: DSM-IV criteria—recurrent episodes of binge eating and recurrent inappropriate compensatory behavior
to prevent weight gain; compensatory behavior can include vomiting, use of laxatives, diuretics, and excessive exercise;
binge eating and inappropriate compensatory behaviors occur ≥2 times/wk for at least 3 mo; self-evaluation
unduly influenced by body shape and weight; disturbance not exclusive to episodes of AN; purging type—use of compensatory
behaviors, eg, vomiting, laxatives, chewing/spitting, diuretics, stimulants; non-purging subtype—use of excessive
exercise or fasting
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| Psychiatric comorbidity of eating disorders
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| Affective disorders: difficult to make primary diagnosis of depression in starving patient; eating must resume before accurate
diagnosis of affective disorder can be made; major depression—starvation can mimic symptoms of depression;
dysthymia—common in patients with eating disorders; perceptual disturbance in how patients view themselves; mood
disorder—possibly secondary to medical condition; bipolar disorder—no specific increase reported in patients with
AN or BN
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| Anxiety disorders: panic disorder—panic attacks can occur before meals or as postbinge anxiety; anxiety occurs in
some patients while eating if watched by someone; obsessive-compulsive disorder (OCD)—increasingly associated
with AN; studies show high-dose fluoxetine (40-80 mg) appears to decrease episodes of binging-purging by 70% to
85%; obsession about food and ritualistic behaviors similar to obsessive thoughts and compulsive behaviors; in BN,
purging behavior linked to compulsive behavior that decreases anxiety associated with obsession; trichotillomania and
attention-deficit disorder (ADD) occur at slightly higher rates in patients with eating disorders; social phobia—
patients preoccupied with how they look to others; fear of going out in public; specific phobia—fears associated with
specific foods
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| Impulse control disorders: impulse control disorder not otherwise specified (ICDNOS)—more common in patients with
BN; intermittent explosive disorder—some affective behaviors that occur during treatment may mimic intermittent
explosive disordered behaviors, but may actually indicate patient improving; trichotillomania—slightly higher occurrence
in patients with BN
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| Thought disorders: classic schizophrenia—no increased incidence in patients with eating disorders; “pseudo-
psychosis”—patients not hallucinating or paranoid as in schizophrenia, but perception of reality skewed; consider using
low-dose neuroleptic, eg, olanzapine (independent of tryptophan metabolism); organic hallucinosis and organic
delusional syndromes—usually secondary to medical complications
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| Substance abuse/dependence: substances abused to alter mental state—increased alcohol abuse and dependence among
bulimia patients; use of opioid medications and benzodiazepines associated with need to avoid feelings about weight,
body, and food; increased rate of stimulant abuse and dependence among patients with eating disorders because of associated
benefits, eg, weight loss, increased energy level, and euphoric feelings; substances abused to counteract
weight gain—diuretics, laxatives, ipecac, opioids, stimulants, and specific foods used to induce laxative effect (eg,
prunes)
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| Personality disorders: increased rates of borderline traits among patients with BN; avoidant and passive/dependent traits
associated with AN; states of starvation and semistarvation can exacerbate subclinical traits; avoid making diagnosis in
starving patient; get adequate history before making diagnosis
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| Sexual dysfunction: more common in patients with eating disorders, possibly because of physical complications (eg, decreased
estrogen and testosterone levels); dysfunction includes delayed orgasm (also associated with depression), decreased
libido, decreased neuroendocrine response, vaginismus, vaginitis, and dyspareunia
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| Organic mental disorders: depletion of central nervous system adipose tissue can decrease neuronal transmission both intraneuronally
and interneuronally; lack of nutritional stability (eg, tryptophan) can deplete neurotransmitter systems
dependent on precursor chemicals
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| Special medical comorbidities: diabetes and BN—patients at risk for hypoglycemic crisis or coma; patient with
compliance issues may need care of specialist; ADD and BN—consider combination of topiramate and bupropion (eg,
Wellbutrin; caution because of increased risk for seizures); speaker recommends referral to psychiatrist for this prescription;
pregnancy and BN—rule out hyperemesis of pregnancy; patients can develop dehydration, severe complications,
miscarriage, and low amniotic fluid levels; manage patient closely; consider severity of bulimia when determining
whether to use selective serotonin reuptake inhibitors (SSRIs) during pregnancy; consider consulting with obstetrician/
gynecologist specializing in high-risk pregnancy before prescribing high-dose SSRI
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| Medical work-up of patient with AN: obtain CBC, electrolyte levels, liver function tests (LFT) with cholesterol and
lipid profile, amylase, fasting blood glucose, renal function tests, and electrocardiography; consider bone density scan,
magnetic resonance imaging or computed tomography in cases of severe emaciation; establish baseline weight; record
height and age
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| Psychotherapy for binge eating/BN: CBT treatment of choice (especially when combined with pharmacotherapy);
interpersonal therapy (IPT) promising in short-term, but not as good as CBT in long-term; antidepressants, especially fluoxetine,
helpful but not more effective than CBT alone; abstinence goal of treatment
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| Management guidelines: for BN—patients should eat 3 meals/day, abstain from alcohol and marijuana, take medications
as prescribed, make list of support persons, and use National Association for Anorexia Nervosa and Associated Disorders
(ANAD) support groups if needed; patients should avoid use of scales, eat with others, and exercise in moderation;
for AN—“food is medicine”; no Food and Drug Administration (FDA)–approved drug for AN; can consider using neuroleptics;
do not let patient’s urge to starve or stay thin become syntonic with goal of treatment; patients should eat with
others; get medical evaluation; discontinue use of empty calories (eg, diet soda)
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Suggested Reading
Altshuler LL et al: Acceleration and augmentation strategies for treating bipolar depression. Biol Psychiatry 53:691,
2003; Bados A et al: The efficacy of cognitive-behavioral therapy and the problem of drop-out. J Clin Psychol 63:585,
2007; Claudino AM et al: Antidepressants for anorexia nervosa. Cochrane Database Syst Rev 25:CD004365, 2006;
Dossett EC et al: Lack of mania prophylaxis associated with lamotrigine monotherapy in manic-predominant bipolar I
disorder. J Clin Psychiatry 68:973, 2007; Frye MA et al: Unmet needs in bipolar depression. Depress Anxiety 19:199,
2004; Fassino S et al: Psychological factors affecting eating disorders. Adv Psychosom Med 28:141, 2007; Gentile S:
Atypical antipsychotics for the treatment of bipolar disorder: more shadows than lights. CNS Drugs 21:367, 2007; Gitlin
MJ: Treatment-resistant bipolar disorder.Bull Menninger Clin 65:26, 2001; Holtkamp K et al: Group psychoeducation
for parents of adolescents with eating disorders: the Aachen program. Eat Disord 13:381, 2005; Kotler LA et al: Emerging
psychotherapies for eating disorders. J Psychiatr Pract 9:431, 2003; Latner JD et al: Cognitive-behavioral therapy
and nutritional counseling in the treatment of bulimia nervosa and binge eating. Nuechterlein KH et al: Classifying episodes
in schizophrenia and bipolar disorder: criteria for relapse and remission applied to recent-onset samples. Psychiatry
Res 144:153, 2006; Eat Behav 1:3, 2007; O'Brien KM et al: Reducing maladaptive weight management practices: developing
a psychoeducational intervention program. Eat Behav 8:195, 2007; Savas HA et al: Atypical antipsychotics as
"mood stabilizers": a retrospective chart review. Prog Neuropsychopharmacol Biol Psychiatry 31:1064, 2007.
Educational Objectives
| The goal of this program is to improve management of atypical bipolar disease and eating disorders such as anorexia
nervosa (AN) and bulimia nervosa (BN). After hearing and assimilating this program, the clinician will be better able
to:
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| 1. Provide evidence for the use of anticonvulsants in treatment-resistant bipolar disorder.
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| 2. Utilize combination strategies for treatment-resistant bipolar disease.
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| 3. Explain why omega-3 fatty acids, calcium channel blockers, electroconvulsive therapy, and psychosocial adjunctive
therapies effectively treat treatment-resistant bipolar disorder.
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| 4. Enumerate the psychiatric and medical comorbidities associated with eating disorders.
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| 5. Describe guidelines for management of patients with AN and BN.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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, the following has been disclosed: Dr. Gitlin is on the Speakers’ Bureaus for GlaxoSmithKline,
Cephalon, Bristol-Myers Squibb, Eli Lilly, and Pfizer.
Acknowledgments
Drs. Gitlin and Richards were recorded on October 6, 2006, in Industry Hills, CA, at the 2006 Behavioral Health Symposium
, sponsored by Southern California Permanente Medical Group. The Audio-Digest Foundation thanks the speakers and
Southern California Permanente Medical Group for their cooperation in the production of this program.
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