PSYCHOPHARMACOLOGY
From Helpful Highlights from Heartsome Heedful Headliners, presented by the University of Wisconsin School of
Medicine and Public Health and the Madison Institute of Medicine, Inc
| BENZODIAZEPINES: SAFE AND EFFECTIVE ANXIOLYTICS OR DRUG FIEND’S DELIGHT ?—David J. Katzelnick,
MD, Clinical Professor of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison;
Distinguished Senior Scientist, Madison Institute of Medicine, Inc; and Chief Executive Officer, Healthcare Technology
Systems, Inc, Madison, WI
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| Anxiety disorders: “we’re not great at treating anxiety disorders”; benzodiazepines may help when used as adjunct to
selective serotonin reuptake inhibitors (SSRIs)
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| Classification of benzodiazepines: select medication based on symptoms being treated; eg, for sleep, select medication
with long half-life; advantages—effective; rapid onset; generally well tolerated; dose easy to adjust; can be
used as needed (prn) for situational anxiety; disadvantages—sedation (some data suggest sedation tends to habituate);
cognitive and psychomotor impairment; interaction with alcohol; physiologic dependence; discontinuation difficulties;
potential for abuse in predisposed individuals; not effective for comorbid depression
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 | F = fast onset of action; I = intermediate onset; S = slow onset
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| Abuse: study data suggest abuse more common in younger patients; benzodiazepines “probably not a good idea, period,”
for people who use alcohol regularly or those with alcohol dependence; issues include recreational use, seeking
high, using very large doses, tolerance, and illicit acquisition; escalation to high dose—in study, observed in only
1.6%; high dose defined as 20 diazepam milligram equivalents (DME); median dose 10 DME, and did not increase
over time; predictors of dose escalation included use of antidepressant or regular use of lorazepam, duplicate prescriptions
filled at different pharmacies, and younger age
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| Discontinuation syndromes: dependence correlates with dose and duration; important to differentiate between recurrence,
rebound, and withdrawal; recurrence—same symptoms as before medication gradually recur as medication
tapered; symptoms may or may not return to previous intensity; indicates that it may be too soon to discontinue medicine
or patient may require another kind of treatment; rebound—some of same symptoms recur, but worse than before
medication; usually of short duration, then return to pretreatment anxiety; withdrawal—qualitatively different from
recurrence and rebound; symptoms (eg, anxiety, insomnia, motor tension) opposite of side effects; patient has perceptual
sensitivity; symptoms seldom severe and recovery complete
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| Managing discontinuation syndromes: substitute longer-acting benzodiazepine; use other agents (eg, β-blockers,
clonidine, carbamazepine) to modify symptoms of discontinuation; provide alternative treatment (eg, cognitive behavioral
therapy) for underlying problem before discontinuing benzodiazepine; taper, taper, taper—all benzodiazepines,
regardless of half-life and speed of absorption, need gradual tapering if taken for more than a few days; hardest
part of tapering is last milligram, because medications do not come in doses <1 mg, and “you end up with these weird
things like chopping pills into pieces”; most patients do well when allowed to control speed of tapering
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| Combining benzodiazepines with antidepressants: SSRIs take time to be effective; adding benzodiazepine allows
rapid relief of anxiety, and benzodiazepine can be tapered as SSRI begins to work; studies show that combination
may work better initially, but some patients fail to discontinue benzodiazepine for unknown reasons, and 30% to 33%
end up being on both medications; European study indicated anxiety independent risk factor for suicide, and benzodiazepine
added to initial SSRI may reduce suicide risk
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| Benzodiazepines and alcohol: benzodiazepines increase sedative effects of alcohol in additive, not synergistic,
way; literature review indicates that combination not more lethal than either alone
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| Benzodiazepine overdose: much harder to kill oneself with just benzodiazepines than with just barbiturates, but if
patient does take large amounts of benzodiazepine, flumazenil (benzodiazepine antagonist) can be administered intravenously;
however, using flumazenil too aggressively can result in sudden drop in benzodiazepine level, causing withdrawal
seizures; when using flumazenil, monitor patient’s ventilation closely; avoid in patient with mixed
benzodiazepine and tricyclic antidepressant overdose
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| Cognitive side effects: include sedation, antegrade amnesia, psychomotor slowing, impaired verbal learning, and impaired
visual-spatial ability; warn all patients taking benzodiazepines about possible impairment in performance while
driving or operating dangerous equipment, especially early on in treatment; most patients experience improved cognitive
functioning with withdrawal from benzodiazepines, but some patients may take >6 mo to return to baseline, and
for a few, cognitive deficits may be permanent
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| Children and adolescents: no controlled trials, only open trials, and those not for anxiety disorders; open studies for
panic and school phobia look positive, but have not been confirmed; benzodiazepines may be helpful over short term,
while slower agents take effect; unknown if benzodiazepines help control initial SSRI activation; the younger the
child, the higher the risk for behavioral activation
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| Benzodiazepines in medical illness: if patient has hepatic disease, use lorazepam, oxazepam, or temazepam; if patient
has chronic obstructive pulmonary disease (COPD), monitor respiration and avoid drugs with longer half-lives;
benzodiazepines contraindicated in sleep apnea; strong evidence that long-term use of benzodiazepines in elderly significantly
(up to 70%) increases risk for hip fractures; agents with short half-lives increase memory loss, so use agents
with intermediate or long half-lives in elderly
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| General principles of benzodiazepine use: benzodiazepines powerful but double-edged sword; before starting
benzodiazepines, develop treatment plan that includes target symptoms and duration of treatment; reassess risks and
benefits before physical dependence occurs; use lowest effective dose and shortest duration; attempt periodic taper,
and taper slowly if use has been long-term
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| OMEGA-3 FATTY ACIDS IN PSYCHIATRY —Marlene P. Freeman, MD, Director, Women’s Mental Health Center,
and Associate Professor of Psychiatry, Obstetrics and Gynecology, University of Texas Southwestern Medical School,
Dallas
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| Brief overview of fatty acids: omega-3 fatty acids are essential long-chain polyunsaturated fatty acids; eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA) derived from marine animals, linolenic acid from plant sources
(linolenic acid not to be confused with linoleic acid, which is omega-6 fatty acid and more than plentiful in American
diets); EPA and DHA more bioavailable than linolenic acid in central nervous system and brain; all studies on benefits
of omega-3 fatty acids have involved EPA and DHA, none have used linolenic acid; omega-3 fatty acids have numerous
confirmed medical benefits, especially in cardiovascular disease
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| American Psychiatric Association (APA) subcommittee on omega-3 fatty acids: invited participants with
expertise in omega-3 fatty acids and psychiatry; examined evidence for omega-3 fatty acids across disorders, critically
evaluated treatment data, and made recommendations for future research
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| Epidemiologic evidence: cross-national analyses demonstrate higher per capita seafood consumption related to
lower prevalence of major depression, depression in pregnancy, postpartum depression, and bipolar disorder
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| Randomized double-blind placebo-controlled trials: only 6 involving omega-3 fatty acids; “they’re extremely
messy in terms of how to interpret them”; designs and doses varied widely; in 4 studies, omega-3 fatty acids better
than placebo; in 4 studies, omega-3 fatty acids were add-on therapy with antidepressants; some studies used EPA
alone, some used DHA alone, and some used combination
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| Depression: meta-analyses demonstrate benefit in unipolar and bipolar depression, but results highly heterogeneous,
and important to examine characteristics of each study to note differences in methodology
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| Premenstrual dysphoric disorder: omega-3 fatty acids might be helpful; evening primrose oil (omega-6 fatty acid) no
better than placebo
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| Schizophrenia: preliminary studies suggested omega-3 fatty acids might help, but meta-analyses have not supported
those findings
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| Borderline personality disorder: in trial of EPA vs placebo, women who took omega-3 fatty acids showed significantly
more improvement in aggressive and depressive symptoms
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| Dementia: no randomized trials; postmortem examinations show reduced omega-3 fatty acids in brains of those with
Alzheimer’s disease; epidemiologic studies generally look at fish intake and correlation with development of dementia,
and must take into consideration socioeconomic status and other factors; Cochrane database review in 2006
concluded that, until randomized trials available, no evidence to support use of omega-3 fatty acids in preventing
dementia or cognitive impairment
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| Attention-deficit/hyperactivity disorder (ADHD): use of omega-3 fatty acids controversial; some studies positive and
some negative; specific constituents of omega-3 fatty acids not studied
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| Subcommittee recommendations: American Heart Association guidelines endorsed because of high comorbidity
between psychiatric disorders and cardiovascular disease; lifestyle factors (eg, smoking, obesity) that increase cardiovascular
risk more common in psychiatric patients; some psychotropic drugs increase metabolic risk; subcommittee
recommends 1) adults should consume fish twice weekly or more often; patients with mood, impulse-control, or psychotic
disorders should consume 1 g/day of EPA plus DHA; supplements of 1 to 9 g/day may be useful in patients
with mood disorders, but patient who takes >3 g/day should be monitored by physician
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| Depression during pregnancy and postpartum period: untreated psychiatric disorders pose risk during pregnancy
and postpartum period, including increased risk for complications related to pregnancy; “there’s almost global
impact on child development [in children who] have a mom who has an untreated psychiatric disorder”; information
about safety of antidepressants during pregnancy confusing and conflicting (less controversy about using antidepressants
during breast-feeding); studies show that women with depression who are euthymic on antidepressant have high
rate of relapse during pregnancy (relapse rate 40% in those who continue to take antidepressant during pregnancy, and
68% in those who discontinue); increased risk for psychiatric hospitalization during postpartum period
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| Suggestions for treatment of pastpartum depression: if depression moderate to severe, treat (discuss risks and
benefits of different treatment approaches with both parents); if medication selected, use lowest effective dose; consult
with experts; if depression mild, consider nonmedication alternatives
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| Omega-3 fatty acids during pregnancy and postpartum period: wish list for antidepressant treatment of
postpartum depression includes effectiveness, safety in pregnancy and breast-feeding, something that mothers and babies
need anyway, no carbohydrates, and pleasant taste (eg, chocolate); depletion of omega-3 fatty acids common during
pregnancy; maternal omega-3 fatty acids selectively transferred to developing fetus for brain and retinal
development; intake of omega-3 fatty acids by pregnant and lactating women in United States usually inadequate
(20%-60% of recommended intake); omega-3 fatty acids already studied during pregnancy and known to be safe and
beneficial; increased rates of preterm delivery observed in women with diets low in omega-3 fatty acids; data suggest
that omega-3 fatty acids may prolong gestation and protect against preterm delivery, and may protect against development
of preeclampsia in mother and cerebral palsy in infant
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| Fish intake and pregnancy: Food and Drug Administration (FDA) recommends that pregnant women avoid tilefish,
swordfish, shark, and king mackerel (due to high levels of mercury sometimes found in these fish); all other fish
safe if intake limited to 12 oz/wk; fish intake during pregnancy has fallen considerably since FDA released these
guidelines in 2003 because women do not pay attention to which species are unsafe; higher fish intake during pregnancy
associated with better cognitive function in infant; taking omega-3 fatty acid supplements eliminates risk for
mercury ingestion (tests of 16 brands of fish-oil capsules showed none contained significant amounts of mercury,
polychlorinated biphenyls [PCBs], or dioxin, and none showed spoilage)
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| Limitations of omega-3 fatty acids: optimal doses in psychiatric disorders unclear; food supplements not regulated
with same vigilance as pharmaceuticals; not usually covered by insurance; fear of mercury in fish
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Selected Reading
Barker MJ et al: Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis.
Arch Clin Neuropsychol 19:437, 2004; Bruce SE et al: Are benzodiazepines still the medication of choice for patients
with panic disorder with or without agoraphobia? Am J Psychiatry 160:1432, 2003; Bruce SE et al: Influence
of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder:
a 12-year prospective study. Am J Psychiatry 162:1179, 2005; Conklin SM et al: High omega-6 and low omega-3
fatty acids are associated with depressive symptoms and neuroticism. Psychosom Med 69:932, 2007; de Haas SL et
al: Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA(A) alpha(2,3) subtype-selective agonist, compared
to lorazepam and placebo in healthy volunteers. J Psychopharmacol 21:374, 2007; Denis C et al: Pharmacological
interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst
Rev 3:CD005194, 2006; Diem SJ et al: Use of antidepressants and rates of hip bone loss in older women: the study of
osteoporotic fractures. Arch Intern Med 167:1240, 2007; Freeman MP et al: Omega-3 fatty acids and supportive
psychotherapy for perinatal depression: A randomized placebo-controlled study. J Affect Disord Jan 16, 2008; [Epub
ahead of print]; Freeman MP et al: Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry.
J Clin Psychiatry 67:1954, 2006; Freeman MP et al: Randomized dose-ranging pilot trial of omega-3 fatty acids
for postpartum depression. Acta Psychiatr Scand 113:31, 2006; Freeman MP, Sinha P: Tolerability of omega-3
fatty acid supplements in perinatal women. Prostaglandins Leukot Essent Fatty Acids 77:203, 2007; Freeman MP:
Omega-3 fatty acids and perinatal depression: a review of the literature and recommendations for future research. Prostaglandins
Leukot Essent Fatty Acids 75:291, 2006; Freeman MP: Omega-3 fatty acids in psychiatry: a review. Ann
Clin Psychiatry 12:159, 2000; Goddard AW et al: Early coadministration of clonazepam with sertraline for panic
disorder. Arch Gen Psychiatry 58:681, 2001; Keck PE Jr et al: Double-blind, randomized, placebo-controlled trials
of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry
60:1020, 2006; Koski A et al: Alcohol and benzodiazepines in fatal poisonings. Alcohol Clin Exp Res 26:956, 2002;
Ross BM et al: Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids
Health Dis 6:21, 2007; Sareen J et al: Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based
longitudinal study of adults. Arch Gen Psychiatry 62:1249, 2005; Simon GE, Ludman EJ: Outcome of
new benzodiazepine prescriptions to older adults in primary care. Gen Hosp Psychiatry 28:374, 2006; Stahl LA et al:
The role of omega-3 fatty acids in mood disorders. Curr Opin Investig Drugs 9:57, 2008.
Educational Objectives
| The goal of this program is to improve management of psychiatric disorders through an exploration of the uses of benzodiazepines
and omega-3 fatty acids. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Select benzodiazepines on the basis of their potency, half-life, and speed of onset of action.
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| 2. Determine which patients are appropriate candidates for treatment with benzodiazepines.
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| 3. Provide a brief overview of omega-3 fatty acids.
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| 4. Discuss the evidence supporting the use of omega-3 fatty acids in patients with psychiatric disorders.
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| 5. Explain why omega-3 fatty acids may be preferable to antidepressants during pregnancy and the postpartum period.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
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. Katzelnick
is a consultant to APA, Forest, Novartis, Pfizer, Schwarz, and Shire; does research for Eli Lilly; is a speaker for Eli Lilly,
Forest, Pfizer, and Schwarz; is a minor stockholder in Johnson & Johnson; and is a principal in Healthcare Technology
Systems, Inc. Dr. Freeman receives honoraria from AstraZeneca and is an investigator for Eli Lilly and Reliant. The
planning committee reported nothing to disclose.
Acknowledgements
Drs. Katzelnick and Freeman were recorded at Helpful Highlights from Heartsome Heedful Headliners, held November
2-3, 2007, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health
and the Madison Institute of Medicine, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors for
their cooperation in the production of this program.
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