MIND SHIFTS
| DEPRESSION —Andrew F. Leuchter, MD, Daniel X. Freedman Professor and Vice-Chair, Department of Psychiatry and
Biobehavioral Sciences, David Geffen School of Medicine at the University of California, Los Angeles
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| Depression and anxiety: two thirds of patients with major depression also have anxiety disorders; one third of depressed
patients have panic attacks; disorders related, and same medications work for both conditions but used somewhat differently
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| Definitions: major depression—characterized by 5 symptoms of depression (eg, depressed mood, anxiety, loss of interest
in usual activities) and physical problems (eg, fatigue, sleep disturbances [particularly early morning awakening],
pain); minor depression—characterized by presence of 2 or 3 symptoms of depression; major depression with
melancholia—characterized by 7 symptoms of depression, with heavy emphasis on physical symptoms; classically responds
well to antidepressants; comment—linear relationship between number of depressive symptoms and degree of
disability
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| Physical symptoms: sleep disorders and lack of energy; two thirds of depressed patients who present to family physician
do not identify depression as primary complaint; patients with only emotional symptoms less difficult to treat; those
with physical complaints more likely to be disabled by depression; underlying physical problems (eg, post myocardial
infarction [MI] state, diabetic neuropathy) in depressed patients more difficult to treat; post-MI depressed patients have
much slower course of recovery and higher 6-mo and 1-yr mortality
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| Response to therapy: defined as ≥50% reduction in symptoms; nonresponse seen in 10% to 15% of patients; most
show partial response; remission goal of therapy; requires at least 75% reduction in symptoms; ≈50% of patients go into
remission with 1 drug, another 20% may respond but have some residual symptoms; others fail to respond or fail to comply
with therapy; remission—important to achieve because depression is relapsing illness; patients in remission generally
asymptomatic for 200 to 250 wk before they experience symptoms again; 76% of patients with residual symptoms
relapse within 10 mo; sequence of response—sleep and energy first things to improve, followed by depressed mood;
citalopram (Celexa) good sedating agent; most common residual symptoms—physical symptoms, eg, sleep problems,
low energy, aches and pains
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| Mixed reuptake inhibitors: antidepressants that affect serotonin and norepinephrine receptors; agents include venlafaxine
(Effexor XR), duloxetine (Cymbalta), and tricyclic antidepressants (TCAs; eg, nortriptyline [Pamelor], amitriptyline
[Elavil]); comments—chief advantage of newer agents (eg, venlafaxine, duloxetine) is lack of anticholinergic side effects
or postural hypotension; TCAs classic drugs for treating patients with pain syndromes (eg, cancer pain, fibromyalgia, diabetic
neuropathy)
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| Antidepressant medications: all agents equally effective in reducing symptoms; however, all not equally effective in
achieving remission or resolving specific symptoms; most drugs work by blocking reuptake of serotonin and norepinephrine;
some block either serotonin or norepinephrine reuptake, while others more balanced; fluoxetine (Prozac) first selective
serotonin reuptake inhibitor (SSRI) released, but far less serotonin-selective than some newer agents (eg,
escitalopram [Lexapro], Celexa); fairly balanced drugs include Effexor, Cymbalta, imipramine (Tofranil), Elavil, and
Pamelor; drugs more selective for norepinephrine include desipramine
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 | Mixed reuptake inhibitors: may be slightly better in getting more serious cases of depression into remission (eg, major
depression with melancholia); overall, balanced and mixed agents probably not any better than more selective agents
for treating depression; however, “fairly conclusive” that mixed or balanced agents better for improving chronic pain,
diabetic neuropathy, and fibromyalgia
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| Serotonergic agents: appear better for treating patients whose depression has features of obsessive-compulsive disorder
(OCD) and menstrually-related mood swings (study showed sertraline [Zoloft] better than desipramine for treating latter);
bupropion [Wellbutrin] may help relieve anxiety, but may also exacerbate anxiety symptoms during first 2 wk
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| Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: large study involving 14 regional
centers and 4000 subjects over 7 yr; in level 1, all patients placed on Celexa; those who did not do well on Celexa
assigned to level 2 and placed on other agents; level 1—patients given accelerated doses of Celexa over 12 to 14
wk, up to 60 mg; average dose of those who responded ≈40 mg; most patients had to be treated for ≈10 wk to achieve
remission; response rate ≈50%, whereas remission rate only ≈33%; comments—1-mo medication changes no longer
supported by data; push drug dosage and encourage patients to “hang in there”; single antidepressant has modest efficacy
in getting people over depression; pushing Celexa to 60 mg relatively safe
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| Managing resistant patients: optimize dose, then consider switching to another antidepressant, adding second antidepressant
(combining), or adding second agent that is not traditional antidepressant (augmenting); strategies for switching
—go from one SSRI to another; switch to antidepressant in another class; remark—switching generally
considered less desirable than combining or augmenting
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| Level 2 of STAR*D trial: patients switched from Celexa to Zoloft, Wellbutrin, Effexor, or cognitive behavioral therapy;
or placed on augmentation therapy with Celexa plus Wellbutrin, buspirone (BuSpar), or cognitive behavioral therapy;
this phase not randomized; among switchers, 20% to 25% of patients did well, regardless of whether switched to drug
of same or different class (those switched to Zoloft did just as well as those switched to Wellbutrin or Effexor); in augmentation
group, adding bupropion slightly more effective than adding buspirone; additional 25% to 30% of patients
on level 2 therapy achieved remission; some patients achieved remission in 4 to 6 wk, while others took longer (up to 6
mo)
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| Take-home messages from level 2: switching, combining, or augmenting all reasonable strategies if first agent does not
work; 3 additional months may be needed to see benefits from change in treatment; mechanism of action not as important
as previously thought; if patient doing well on first drug, probably best to add second drug, rather than switch
drugs; whatever is done will help most patients get well
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| General principles for combining or augmenting: if patient tolerates first drug and shows some improvement, add second
drug; ascertain type of side effects; if patient experiencing sexual problems, consider adding bupropion (studies show
sexual dysfunction resolved in one third to one half of patients); if patient anxious, consider adding buspirone; if patient
having sleep problems, consider adding paroxetine [Paxil]); avoid drug-drug interactions; make dosing convenient;
allow time for onset of action
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| Agents used for augmentation: established efficacy—lithium (effective, but associated with weight gain and tremors);
triiodothyronine (T3 ; Cytomel, 25 to 50 µg if thyroid-stimulating hormone [TSH] borderline high; better than levothyroxine
[T4 ; Synthroid]); bupropion to counter sexual side effects; probably effective—olanzapine (Zyprexa) 2.5 mg (for
patients with anxiety and sleep problems; watch for weight gain and metabolic problems); modafinil (Provigil; helps overcome
sedation)
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| Questions and answers: lamotrigine (Lamictal)—not approved for treating depression, but appears to work well in
treating bipolar and unipolar depression; effective dose 25 to 100 mg; starting dose 25 mg, can increase by 25 mg every 2
wk; side effects minimal; STAR*D trial—not placebo controlled; depression during pregnancy—try to avoid antidepressants,
but fluoxetine and bupropion appear safe; risk for low birth weight; consult with psychiatrist; avoid lithium,
most mood stabilizers, and anticonvulsants; antidepressants losing effectiveness over time—may happen up to
20% of time; may begin happening at ≈6 mo of therapy; highest “poop out” rate with SSRIs; treating depression for
life—strongly advised after third depressive episode; consider in patients with strong family history
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| SCHIZOPHRENIA —Roger J. Cadieux, MD, Clinical Professor of Psychiatry, Pennsylvania State University College of
Medicine, Hershey, PA
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| Introduction: schizophrenia most devastating lifelong disorder; chances for patient living better life much greater if
strong therapeutic alliance developed with health professional; this takes years, as patients do not trust easily; each time
patients have remission (after exacerbation), they do not get back to previous baseline level; schizophrenia characterized
by aberrant behavior; no pathognomonic signs; often diagnosis of exclusion; not easily categorized
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| Prevalence: accounts for 22% of hospital admissions; 10% of prison population have schizophrenia (10 times prevalence
in general population) and 33% of homeless
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| Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria: ≥2 positive or negative
symptoms, each present for ≥1 mo; continuous signs of disturbance, persisting for at least 6 mo; social and occupational
dysfunction
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| Positive symptoms: agitated behavior; hallucinations and delusions; bizarre behavior; thought disorders (eg, fragmented
thoughts, thoughts that make no sense); negative symptoms—social withdrawal; affective blunting; alogia (ie,
blunting of speech); avolition (ie, loss of will, energy, drive); anhedonia (lack of pleasurable feelings); negative symptoms typically
cause patients to “hide out” and not interact with others; older drugs (eg, thioridazine [Mellaril]) do not treat negative
symptoms
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| Phases of schizophrenia: prodromal—insidious onset over months or years, with subtle behavioral changes; active
signs—psychotic symptoms, leading to medication intervention; residual—as patients age, positive symptoms lost,
but negative symptoms persist
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| Clinical subtypes: paranoid; disorganized; catatonic; undifferentiated (mixture); often not helpful because patients
move in and out of subtypes
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| Epidemiology: lifetime prevalence 1% to 2.5%; crosses all cultural, socioeconomic, educational, and financial barriers;
mean age of onset earlier in men than in women; highest rate seen among those in lower socioeconomic class (many
schizophrenics drift downward into lower socioeconomic class because of unemployment)
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| Mortality: schizophrenia associated with 2-fold increase in mortality; 1 in 3 patients attempt suicide, and 1 in 10 succeed;
mortality rate for both self-inflicted and secondary disease 1.5 to 4 times higher than general population, 4 times higher
for unnatural causes (eg, suicide, accidental death); overall life expectancy 20% shorter than for general population
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| Etiology: several hypotheses; genetics plays significant role (concordance rate 14% in dizygotic twins and 46% in
monozygotic twins); lifetime prevalence 5% to 6% if one parent schizophrenic and 46% if both parents schizophrenic
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| Therapeutic goals: prevent patient from harming self or others; control disturbed behaviors; suppress symptoms;
achieve return to best level of functioning; develop therapeutic alliance with patient; formulate short- and long-term treatment
goals; connect patient with community resources
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| Treatment issues: 30% of patients respond poorly to treatment; noncompliance rate 50% in first year; highest response
rate 25% to 30%; if untreated or compliance poor, 70% of patients remit within first year; 50% of patients have history of
substance abuse
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| Predictors of poor outcome: social isolation; long duration of episode; history of past psychiatric treatment; being unmarried;
history of childhood behavioral problems
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| Comorbidities: depression and suicide; substance abuse (tobacco and alcohol main drugs abused); metabolic syndrome;
various physical illnesses
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| Interventions: newer atypical agents act on serotonergic and dopaminergic receptors, whereas older agents act only on
dopamine receptors; target symptoms carefully; in resuming therapy, use agents that have worked in past, but do not go back to
older typical agents; use newer agents to avoid tardive dyskinesia and to treat negative symptoms; minimum trial for each
agent 4 to 6 wk; concomitant use of >1 antipsychotic not appropriate; several months of therapy required to achieve desired effects
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| Antipsychotic drugs: older agents (eg, perphenazine [Trilafon]) associated with movement disorders; clozapine (Clozaril)
seldom used, unless patient has unrelenting hallucinations; risperidone, olanzapine, quetiapine, ziprasidone, and
aripiprazole agents used today; avoid haloperidol (Haldol); when switching from older to newer agents, slowly increase
new drug while decreasing old drug
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| Cardiovascular effects of schizophrenia: significant; patients abuse food as well as tobacco and alcohol, so particularly
prone to developing diabetes and obesity and have 2 times increased mortality from cardiovascular disease
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| Metabolic syndrome: characterized by obesity, decreased high-density lipoprotein (HDL), elevated triglycerides, increased
blood pressure and high fasting blood glucose; antipsychotics particularly associated with weight gain include
clozapine and olanzapine, followed by risperidone and quetiapine; aripiprazole and ziprasidone weight neutral (preferred
first-line drugs for someone with weight problem); ziprasidone and olanzapine available in oral and intramuscular
(IM) formulations (indicated for emergencies); depo formulation now available for risperidone
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| Characteristics of newer atypical agents: lower risk for extrapyramidal symptoms and tardive dyskinesia, minimal elevation
of prolactin (except risperidone); increased sedation, weight gain, anticholinergic and agranulocytic effects with
clozapine; treat negative symptoms of schizophrenia; comments—newer agents not perfect drugs; frequent brief visits
for monitoring required; extrapyramidal side effects and neuroleptic malignant syndrome seen mostly with older
agents
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| Maintenance therapy: essential; prevention of relapse more important than risk for side effects; lifelong therapy indicated
for patients who pose danger to selves or others; involve patients in support programs and vocational training
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| When to hospitalize: when control of symptoms and titration of drugs difficult; when patient poses danger to self or
others; when medication side effects become disabling; remark—frequent office visits (at least once every 3 mo) reduce
need for hospitalization
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Educational Objectives
| The goal of this program is to educate the listener about depression and schizophrenia. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Identify the emotional and physical manifestations of depression.
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| 2. Describe the treatment of depressed patients, using mixed reuptake inhibitors and selective serotonin reuptake inhibitors.
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| 3. Discuss the therapeutic rationale for switching a patient from one antidepressant to another or using combination or
augmentation therapy.
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| 4. Review the clinical manifestations of schizophrenia.
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| 5. Summarize the advantages of the newer atypical antipsychotic agents over the older typical agents in treating schizophrenia.
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Discussed on This Program
Amitriptyline HCl [Elavil]
Aripiprazole [Abilify]
Bupropion HCl [Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban]
Buspirone HCl [BuSpar]
Citalopram HBr [Celexa]
Clozapine [Clozaril, FazaClo]
Desipramine HCl [Norpramin]
Duloxetine [Cymbalta]
Escitalopram oxalate [Lexapro]
Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules]
Haloperidol [Haldol, Haldol Decanoate 50, Haldol Decanoate 100]
Imipramine HCl [Tofranil]
Lamotrigine [Lamictal, Lamictal Chewable Dispersible]
Liothyronine sodium (T3 ) [Cytomel, Triostat]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Modafinil [Provigil]
Nortriptyline HCl [Aventyl HCl, Aventyl HCl Pulvules, Pamelor]
Olanzapine [Zyprexa, Zyprexa Intramuscular, Zyprexa Zydis]
Paroxetine HCl [Paxil, Paxil CR, Pexeva]
Perphenazine
Quetiapine fumarate [Seroquel]
Risperidone [Risperdal, Risperdal Consta, Risperdal M-TAB]
Sertraline HCl [Zoloft]
Thioridazine HCl [Mellaril]
Venlafaxine HCl [Effexor, Effexor XR]
Ziprasidone HCl [Geodon]
Suggested Reading
Ables AZ, Baughman OL III: Antidepressants: update on new agents and indications. Am Fam Physician 67:547,
2003; Armenteros JL, Davies M: Antipsychotics in early onset schizophrenia: systematic review and meta-analysis.
Eur Child Adolesc Psychiatry 15:141, 2006; Bergman RN, Ader M: Atypical antipsychotics and glucose homeostasis.
J Clin Psychiatry 66:504, 2005; Cipriani A et al: Fluoxetine versus other types of pharmacotherapy for depression.
Cochrane Database Syst Rev (4)CD004185, 2005; Friedman ES et al: Presenting characteristics of depressed
patients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res 40:59, 2006;
Ham P et al: Treatment of panic disorder. Am Fam Physician 71:733, 2005; Harrington L et al: Theory of mind
in schizophrenia: a critical review. Cognit Neuropsychiatry 10:249,2005; Hennekens CH et al: Schizophrenia and
increased risks of cardiovascular disease. Am Heart J 150:1115, 2005; Ilott R: Does compliance therapy improve use of
antipsychotic medication? Br J Community Nurs 10:514, 2005; Insel TR: Beyond efficacy: the STAR*D trial. Am J
Psychiatry 163:5, 2006; Kubicki M et al: Evidence for white matter abnormalities in schizophrenia. Curr Opin Psychiatry
18:121, 2005; Loh C et al: A comprehensive review of behavioral interventions for weight management in
schizophrenia. Ann Clin Psychiatry 18:23, 2006; Marcus SM et al: Gender differences in depression: findings from
the STAR*D study. J Affect Disord 87:141, 2005; Margolese HC et al: Tardive dyskinesia in the era of typical and
atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry
50:703, 2005; Preston E, Hansen L: A systematic review of suicide rating scales in schizophrenia. Crisis 26:170,
2005; Rush AJ et al: Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med
344:1231, 2006; Rush AJ et al: Comorbid psychiatric disorders in depressed patients: demographic and clinical features.
J Affect Disord 87:43, 2005; Ryan D et al: Depression during pregnancy. Can Fam Physician 51:1087, 2005;
Thibault JM, Steiner RWP: Efficient identification of adults with depression and dementia. Am Fam Physician
70:1101, 2004; Trivedi MH et al: Factors associated with health-related quality of life among outpatients with major
depressive disorder: a STAR*D report. J Clin Psychiatry 67:185, 2006; Trivedi MH et al: Medication augmentation
after the failure of SSRIs for depression. N Engl J Med 23:354, 2006; Zisook S et al: Use of bupropion in combination
with serotonin reuptake inhibitors. Biol Psychiatry 59:203, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Leuchter has financial relationships with Aspect Medical Systems, Eli Lilly and Company, Glaxo-Smith-Kline,
Wyeth Pharmaceuticals, Pfizer Inc, and Merck Pharmaceuticals.
Dr. Leuchter was recorded in Los Angeles, CA, on June 8, 2006, at the annual Family Practice Refresher Course,
sponsored by the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Cadieux spoke March
29, 2006, at the annual spring Family Practice Review, sponsored by the Temple University School of Medicine, and
held in Lancaster, PA. The Audio-Digest Foundation thanks the speakers and the sponsors for making this program possible.
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