PHARMACOTHERAPEUTIC FACTS OF LIFE
From Limitless Learning from Lively Laudable Luminaries, presented by the University of Wisconsin School of
Medicine and Public Health and the Madison Institute of Medicine, Inc.
| EMERGENT TREATMENT OPTIONS IN TREATMENT-RESISTANT DEPRESSION —Mark H. Rapaport, MD,
Chair, Department of Psychiatry and Mental Health, Cedars-Sinai Medical Center, and Professor of Psychiatry, the
David Geffen School of Medicine at the University of California, Los Angeles
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| Introduction: 1 in 5 individuals will suffer from episode of major depressive disorder; common worldwide (for individuals
18 to 45 y of age, single greatest source of disability [greater than infectious diseases and all others]); studies
show that people with even minor depression at higher risk for cardiovascular and cerebrovascular diseases; also,
bodily illnesses affect brain, and brain diseases affect body; depression highly heterogeneous
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| “Ideal” antidepressant: efficacious; tolerable; works well in children and elderly (as well as in other age groups);
improves symptoms and functioning; few drug interactions; rapid onset of action; safe in overdose; simple to administer;
minimal side effects; treats spectrum of disorders; cost effective; usable for long-term maintenance; does
not exist, but important to keep these qualities in mind
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| Current classes of antidepressants: inhibit norepinephrine, serotonin, or both; a few also affect dopamine;
speaker opines that current treatments palliative, not curative
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| Sequenced Treatment Alternatives to Relieve Depression (STAR*D): complicated study; all results not yet
completely analyzed; in general, showed that having unresolved symptoms after treatment with antidepressant common;
over time, ≈60% of patients in trial met remission criteria, but fewer than one third remained in remission at 6
mo
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| Medical comorbidity: common with depression, and the higher the burden score on the Cumulative Illness Rating
Scale, the less likely someone will respond to antidepressants
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| Treatment resistance: only 30% to 40% of patients remit with first treatment for depression; up to half of treatment
resistance due to improper dosing or to medication nonadherence; psychoeducation important; targeted psychotherapies
may work even when medications have failed; treatment resistance increases with chronicity of
depression; in assessing treatment resistance, determine whether dose and duration of previous treatments adequate;
healing from severe chronic depression takes time
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 | Lithium: theoretically potentiates serotonergic system and modulates variety of second-messenger systems; works
to augment tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake
inhibitors (SSRIs); average response rate in studies 50%; risk for toxicity (try to keep blood levels at ≈0.5
mEq/L); usual time to response ≤2 wk
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| Thyroid hormone: T3 (liothyronine) usually preferable to T4 (levothyroxine); potentiates noradrenergic activity; may
down-regulate T4 in brain; most studies done with TCAs; large study using thyroid hormone to augment SSRIs equivocal;
response rate ≈50%; usual dosage 25 to 50 µg/day
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| Desipramine: if used to augment SSRIs, monitor blood levels of desipramine, which can be elevated by some SSRIs
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| Mirtazapine: successfully used as augmentation strategy in STAR*D; augmentation dosage significantly lower
than for mirtazapine as monotherapy
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| Stimulants: thought to potentiate noradrenergic activity; most data from case series or case reports; usual dosages—
methylphenidate 10 mg tid, dextroamphetamine 5 mg tid, modafinil 100 to 400 mg/day
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| Atypical antipsychotics: not included in STAR*D or most other large augmentation trials; rationale for their use is
possible increase in serotonergic output into frontal cortex and reversal of some SSRI-induced inhibitory effects on
noradrenergic neurons; small study of olanzapine-fluoxetine combination showed patients who received combination
“did remarkably well and improved very, very rapidly”; larger study unable to replicate these results (but
didn’t choose treatment-refractory patients); open-label study of ziprasidone augmentation of SSRI showed 50%
response rate, but no double-blind studies conducted; another study in which risperidone used to augment citalopram
showed risperidone not superior to placebo in maintaining remission
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| Monoamine oxidase inhibitors: effective, but many drug interactions and side effects; monoamine oxidase A
(MAO-A) present in brain, intestine, liver, and placenta; monoamine oxidase B (MAO-B) present in brain, platelets,
lymphocytes, and placenta; proportions of MAO-A to MAO-B different in different organ systems; substrates
for MAO-A serotonin, norepinephrine, dopamine, and tyramine; for MAO-B, phenylethylamine, histamine,
dopamine, and tyramine; crossover occurs in substrates; moclobemide, reversible selective MAO-A agent, not
available in United States; selegiline, MAO-B–selective agent used as antiparkinson medication, tried as antidepressant
in small studies, but at doses at which antidepressant action occurs, it loses its selectivity; selegiline transdermal
system (EMSAM) allows selegiline to bypass intestine and liver, moderating or eliminating some side
effects; transdermal patch (20 mg/cm2 size) delivers equivalent of 6 mg/day of selegiline; no dietary restrictions
with 6-mg/day patch; same restrictions on other medications as with oral selegiline
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| Nonpharmacologic augmentation strategies: vagus nerve stimulation (VNS)—first 60 people treated had severe
treatment-resistant depression and “didn’t get well with anything”; over 24-mo follow-up, response seen in
≈45% and remission in 25%; “and for those people who do get better, it’s remarkable how much better they get”;
subsequent short- and long-term studies continue to show benefit; transcranial magnetic stimulation (TMS)—
magnet near brain makes superficial changes in electric field around brain; results of early studies did not meet criteria
for Food and Drug Administration (FDA) approval, but studies continue; psychotherapy—very important in
people with refractory depression, whether or not they receive other therapies
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| Future therapies: studies suggest that patients with treatment-refractory depression and history of childhood trauma
respond better to psychotherapy than to pharmacotherapy, and best to combination of both; genomics—more information
being discovered about genes associated with vulnerability to depression and about genes of resilience
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| Summary: major depressive disorders are heterogeneous syndromes; current therapies palliative rather than curative;
transition being made to more organized approach to treatment; new approaches abound
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| SOMETHING BAD ABOUT EVERYTHING: MEDICATION RISKS —James W. Jefferson, MD, Clinical Professor
of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison
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| Lithium: has antiviral effect against DNA viruses; requires monitoring of blood levels, but new finger-stick device
on market (InstaRead Lithium System) allows lithium levels to be assessed in office, producing results faster than
traditional laboratory test; essential to monitor kidney function; may interfere with thyroid and parathyroid function
(thyroid interference more likely in women than in men); lithium may cause elevated calcium level as incidental
finding; can cause cognitive impairment, even if blood level not above therapeutic range; many people notice they
are “a bit dull; their reaction time isn’t as fast; they’re not as crisp; they’re not as clear”; these side effects may be
subtle enough not to be noticeable to clinician, but may cause patient to become careless about medication compliance;
tremors—benign essential tremor seldom becomes troublesome, but if it does, try switching to delayed-release
preparation or augmenting with β-blocker or, in rare cases, primidone (Mysoline); extrapyramidal tremor
sometimes occurs; cerebellar-related tremor results from lithium toxicity; metabolism—causes weight gain; skin
disorders—makes acne and follicular keratosis worse, and psoriasis more resistant to treatment; on other hand, evidence
suggests lithium can speed healing of herpes simplex and improve seborrheic dermatitis; toxicity—“kidney
toxicity bad”; neurotoxicity can result in permanent neurologic disability, generally with cerebellar syndrome; drug
interactions—interacts with many drugs, most of which are prescribed by nonpsychiatrists not familiar with lithium;
possible culprits—include thiazide diuretics, perhaps other diuretics; most nonsteroidal anti-inflammatory
drugs (NSAIDs); angiotensin-converting enzyme inhibitors; angiotensin-receptor antagonists; “anything that ends
in ‘statin’”; metronidazole (eg, Flagyl); acetazolamide; xanthines; mannitol; sodium bicarbonate; odd cases—2
cases of lithium toxicity reported after patients given intramuscular ziprasidone; one case reported after intravenous
acyclovir
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| Divalproex (Depakote): extended-release (ER) formula approved for mixed episodes in patients with bipolar disorder;
with regular divalproex, obtain trough level 12 hr after last dose; with ER formulation, 18 hr after last dose;
“black-box” warnings—hepatotoxicity (“not much of a problem in adults”); teratogenicity, especially if taken during
first trimester; pancreatitis (rare; no need to monitor pancreatic enzymes, but if patient develops gastrointestinal
symptoms such as abdominal pain and vomiting, assess liver and pancreatic function); laboratory monitoring—
divalproex blood level; complete blood cell count (CBC); platelets; side effects—cognitive impairment (uncommon;
most studies done in patients taking divalproex to treat epilepsy); dementia and sometimes parkinsonian
symptoms (usually develop after many months of treatment, and clinician may not realize association with divalproex);
tremor similar to that of lithium; weight gain; hair loss (said to be transient; lore suggests risk for hair loss
reduced by supplementing diet with zinc and selenium); curling of straight hair (“a very obscure side effect”); polycystic
ovary syndrome—in studies, 10% of women had oligomenorrhea and elevated androgen levels, but on ultrasonography,
no more cysts on ovaries than in controls; drug interactions—aspirin can increase level of free
valproate 4-fold; aspirin and valproate interfere with platelet function; carbamazepine has complex interaction with
valproate, “but sometimes a nice combination for treatment resistance”; blood level of lamotrigine doubles in presence
of valproate
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| Carbamazepine: initially speeds up its own metabolism (dose may have to be increased after 10 days to 3 wk);
black-box warnings—destruction of bone marrow (rare); leukopenia (usually gradual); thrombocytopenia (carbamazepine
known to cause rash; assess carefully to determine whether it really is rash or petechiae of thrombocytopenia);
side effects—liver problems rare; rash fairly common; teratogenesis; hyponatremia (if patient “looks a
little neurologically impaired” or has seizure, obtain sodium level immediately); drug interactions—
“carbamazepine will interact with most everything”; in presence of calcium channel blocker, reduce carbamazepine
dose
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| Gabapentin: short half-life; prodrug (XP13512) under development that promises to increase half-life of gabapentin;
side effects—somnolence; fatigue; ataxia; dizziness; at higher doses, weight gain; fecal and urinary incontinence reported
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| Lamotrigine: also induces own metabolism, but “nobody cares because the titration of the drug is so gradual that
you’ll never really notice it”; inhibits dihydrofolate reductase; can interfere with folate metabolism, but unknown
whether that has clinical significance (folate supplementation recommended in patient taking any antiepileptic drug);
in rats, binds with melanin in eye, but clinical significance unknown; no evidence that lamotrigine causes ocular
problems in humans; pregnancy—lamotrigine levels decrease as pregnancy progresses; neurology literature reports
breakthrough seizures when lamotrigine dose not adjusted upward as pregnancy progresses; unknown if breakthrough
episodes occur in bipolar disorder; after pregnancy, lamotrigine levels “pop right back up,” but unknown if
this increases risk for rash; side effects—fatigue; no weight gain; benign rash (can progress to Stevens-Johnson syndrome);
drug interactions—can lower valproate level by 25%; carbamazepine, phenytoin, phenobarbital, and oral
contraceptives (OCs) reduce lamotrigine level by half
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| Oxcarbazepine (Trileptal): side effects tend to be milder than those of carbamazepine, except for hyponatremia,
which is more likely with oxcarbazepine; few drug interactions; lowers level of ethinyl estradiol by ≈50%, so
women on OCs may have breakthrough bleeding and are more susceptible to becoming pregnant
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| Topiramate: kidney stones reported in 1.5% of patients taking topiramate for epilepsy (risk higher in men than in
women); also, when used in high doses, rate of intolerability 30%; causes weight loss; psychiatric side effects (nervousness,
depression) dose dependent; uncommon but serious side effects—angle-closure glaucoma; oligohidrosis
and hypothermia; metabolic acidosis
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Suggested Reading
Bauer M et al: World Federation of Societies of Biological Psychiatry (WFSBF) Task Force on Treatment Guidelines
for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines
for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive
disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry 3:69,
2002; Ciusani E et al: Combination therapy with venlafaxine and carbamazepine in depressive patients not responding
to venlafaxine: pharmacokinetic and clinical aspects. J Psychopharmacol 18:559, 2004; Gumnick JF,
Nemeroff CB: Problems with currently available antidepressants. J Clin Psychiatry 61(Suppl 10):5, 2000;
Iosifescu DV et al: The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry
160:2122, 2003; Jefferson JW: Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder).
J Clin Psychiatry 62(Suppl 1):50, 2001; Jefferson JW: Lamotrigine in psychiatry: pharmacology and
therapeutics. CNS Spectr 10:224, 2005; Kessler RC et al: Lifetime prevalence and age-of-onset distributions of
DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593, 2005; Kessler
RC et al: National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from
the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095, 2003; Kessler RC et al: Prevalence, severity,
and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen
Psychiatry 62:617, 2005; McIntyre J, Moral MA: Spotlight on lamotrigine for depression. Drug News Perspect
19:427, 2006; Pande AC, Jefferson JW et al: Efficacy of the novel anxiolytic pregabalin in social anxiety disorder:
a placebo-controlled, multicenter study. J Clin Psychopharmacol 24:141, 2004; Rapaport MH et al: Effects
of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed
by double-blind continuation. Neuropsychopharmacology 32:1208, 2007; Trivedi MH et al: STARD Study
Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STARD: implications
for clinical practice. Am J Psychiatry 163:28, 2006; Van Ameringen M et al: Topiramate augmentation in
treatment-resistant obsessive-compulsive disorder: a retrospective, open-label case series. Depress Anxiety 23:1,
2006.
Educational Objectives
| The goals of this program are to improve the management of treatment-resistant depression by using suggested augmentation
strategies and to optimize pharmacotherapy by reminding clinicians of possible negative effects of various
psychoactive drugs. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Explain the physiologic action of antidepressant medications.
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| 2. Describe pharmacologic augmentation strategies for treatment-resistant depression.
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| 3. Discuss the use of vagus nerve stimulation and transmagnetic cranial stimulation in treatment-resistant depression.
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| 4. Detail the negative effects of lithium.
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| 5. Enumerate the negative effects of several anticonvulsant medications.
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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. Rapaport is an advisor
to Brain Cells and Schwarz Pharmaceuticals; is on the advisory boards of Forest Laboratories, Pfizer, and Solvay;
is a speaker for Cyberonics and Wyeth; and is a relapse-board member for Janssen. Dr. Rapaport discussed off-label
uses of several drugs. Dr. Jefferson receives grant/research support from BMS, Eli Lilly, Forrest, GSK, Janssen, Novartis,
Organon, Pfizer, Roche, Solvay, UCB, and Wyeth; is a consultant for GSK, Organon, Schwarz, and Shire; is a
speaker for Abbott, AstraZeneca, BMS, Eli Lilly, Forest, GSK, Pfizer, Schwarz, Shire, and Wyeth; is a minor stock
shareholder in BMS, GSK, and SciClone; and is a principal in Healthcare Technology Systems.
Acknowledgements
Drs. Rapaport and Jefferson were recorded at Limitless Learning from Lively Laudable Luminaries, held March 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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