Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1356 – 1358 Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer Margaret T. Susce, Elaina Murray-Carmichael, Jose de Leon ⁎ University of Kentucky, Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA Available online 24 April 2006 Codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. Codeine is a much weaker agonist at μ opioid receptors than
DeshmuhkRASHMI DESHMUKH, MD
KATHLEEN FRANCO, MD*
Department of Psychiatry and Psychology, Head, Section of Consultation-Liaison The Cleveland Clinic Psychiatry, Department of Psychiatry andPsychology, The Cleveland Clinic Managing weight gain as a side
effect of antidepressant therapy
■ A B S T R AC T
EIGHT GAIN IS A SERIOUS concern for W patients starting or already taking an
Weight gain caused by antidepressant drugs is a major antidepressant. Weight gain as a side effect of reason for patient noncompliance with treatment and poor antidepressant therapy 1–5 in the short term (3 treatment outcome. Knowing which drugs are more likely to to 6 months) and the long term (1 year or cause weight gain in the short term and the long term is longer) contributes to the reluctance ofpatients to continue or start treatment.2 essential to any discussion with the patient about the risks Knowing how likely an antidepressant is vs the benefits of antidepressant therapy. Informing the to cause weight gain (TABLE 1) helps the physi-
patient up front about the chances of weight gain and cian select the best drug for the individual what can be done if it occurs helps build a strong patient. Informing the patient about the physician-patient relationship and promotes good chances of weight gain and what can be done treatment outcomes.
about it helps build a strong physician-patientrelationship and improves the effectiveness of ■ K E Y P O I N T S
Tricyclic antidepressants and irreversible monoamine ■ MONOAMINE OXIDASE INHIBITORS
oxidase inhibitors (MAOIs) are more likely to cause weightgain in both the short term (< 6 months) and the long term Monoamine oxidase inhibitors (MAOIs) (≥ 1 year). Reversible MAOIs are less likely to cause weight inhibit an enzyme involved in the metabolism gain but are not available in the United States.
of biogenic amines (eg, norepinephrine, epi-nephrine, dopamine, serotonin) and xenobiot- Selective serotonin reuptake inhibitors (SSRIs) are not likely ic amines (eg, tyramine, ephedrine, phenyl- to cause weight gain if used for 6 months or less. Opinions ephrine). They are effective against depression vary as to whether they cause weight gain when used for 1 and anxiety.
MAOIs that bind irreversibly to receptors year or longer. Paroxetine may be more likely than other (eg, phenelzine, isocarboxazid, tranylcypro- SSRIs to cause weight gain.
mine) typically cause weight gain, and this isperhaps more common with phenelzine than For long-term therapy, nefazodone is less likely to cause with isocarboxazid and tranylcypromine.2,6–8 weight gain than SSRIs and tricyclic compounds.
Reversible MAOIs are less likely to causeweight gain but are currently unavailable in In general, bupropion is more likely to cause weight loss, the United States.2 and for long-term therapy it is less likely than SSRIs tocause weight gain.
■ TRICYCLIC ANTIDEPRESSANTS
Weight gain is a common and well-knownadverse effect of short-term and long-termtreatment with tricyclic antidepressants,2 pri- *The author has indicated that she is on the speakers' bureau of the Pfizer company.
marily as a result of excessive appetite. Possible ANTIDEPRESSANTS AND WEIGHT GAIN
DESHMUKH AND FRANCO
Effect of antidepressant drugs on body weight
EFFECT ON WEIGHT
Monoamine oxidase inhibitors Weight gain likely in short term (< 6 months) and long term (≥ 1 year)
Weight gain likely in short term and long term Selective serotonin reuptake
Weight gain in short term less likely inhibitors (SSRIs) other than
Weight gain in long term possible, but evidence is varied Weight gain in short and long term more likely than for other SSRIs Likely to have no effect on weight Likely to cause weight loss More likely than placebo to cause weight gain in short term,but less likely than tricyclics Likely to have no effect on weight mechanisms include blockade of histamine H1 tonin reuptake inhibitors (SSRIs), or no anti- and serotonin 2C receptors, carbohydrate depressant treatment.12 All drug groups craving caused by alpha-noradrenergic activi- showed mean weight changes of less than 2.1 ty or histamine blockade, changes in the regu- lb after 6 months of therapy. Whether or not lation of body fat stores by modulating neuro- these findings can be generalized to communi- transmitter systems at the hypothalamic level, ty patients is unclear.
and recovery from clinical depression.2,5,9,10 Because tertiary tricyclic antidepressants ■ SELECTIVE SEROTONIN REUPTAKE
such as amitriptyline, imipramine, and dox- epin are stronger histamine blockers than are alliance is
secondary tricyclics such as desipramine and Weight gain is less likely with SSRIs when integral to
nortriptyline, the tertiary tricyclic drugs are they are used for 6 months or less. There are more likely to cause weight gain.
diverse opinions about whether increases in In a randomized study of hospitalized body weight occur in patients using them for 1 depressed patients, Fernstrom and Kupfer10 year or longer. Paroxetine may be more likely reported that treatment with three tricyclic than other SSRIs to cause weight gain during compounds promoted weight gain, with short-term or long-term treatment.
amitriptyline adding more weight than nor- Weight change induced by SSRIs is prob- triptyline and desipramine. In the same study, ably related to alteration in serotonin 2C most patients treated with zimelidine (a tri- receptor activity, appetite increase, carbohy- cyclic antidepressant, not available in the drate craving, or recovery from clinical depres- United States) showed no weight gain and often demonstrated weight loss.
In one large placebo-controlled study,15 A study by Frank et al11 indicated that outpatients with depression treated with fluox- 13% to 15% of imipramine-treated patients etine for 12 weeks lost 0.3 kg on average. Croft gained 10 or more pounds by week 16 or 33 of et al16 documented a loss of 0.8 kg with sertra- treatment. In contrast, at least one study of line vs 1.1 kg with bupropion in a placebo-con- nursing home residents found no measurable trolled 12-week comparison. On the other difference in weight outcomes after treatment hand, Mackle and Kocsis,17 in a study lasting with tricyclic antidepressants or selective sero- fewer than 8 weeks, reported a weight gain of 616 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 70 • NUMBER 7 JULY 2003 ANTIDEPRESSANTS AND WEIGHT GAIN
DESHMUKH AND FRANCO
0.5% in patients taking the SSRI citalopram vs 0.9% in those taking placebo. Bouwer andHarvey,14 in an open-label study without Nefazodone seems to be less associated with placebo control, reported a rapid appetite weight gain than other antidepressants in increase and an average weight gain of 7.1 kg studies of both short-term and long-term ther- with citalopram, which is well known to have apy. It is a phenylpiperazine with selective a marked affinity for histamine H1 receptors serotonin and norepinephrine reuptake inhi- and, therefore, stimulates the appetite.
In nursing home patients, SSRIs are as A 36-week placebo-controlled study24 likely to cause weight gain as they are to cause reported weight gain associated with nefa- weight loss, but the magnitude of the effect is zodone to be similar to placebo (7.6% vs 8.6%).
generally small.12 Studies of short-term anti- Sussman et al25 conducted a pooled analy- depressant therapy have suggested that weight sis of three clinical trials comparing nefa- gain is less likely to occur when SSRIs are zodone with SSRIs and three clinical trials used in the short term (3 to 6 months). When comparing nefazodone with imipramine.7,18,25 weight gain does occur, the rates are compara- Using 7% or greater weight change as a mea- ble with those of placebo.2 sure of clinical significance, results indicated Clearly, there is uncertainty about whether that 4.3% of SSRI-treated patients had lost unexpected increases in body weight occur dur- weight at some point in the acute phase (6 to ing long-term treatment as opposed to short- 8 weeks) vs 1.7% with nefazodone. During term treatment with SSRIs.18 In its revised longer treatment (16 to 46 weeks), weight practice guideline for the treatment of major gain occurred more often in patients taking an depressive disorder,19 the American Psychiatric SSRI than in patients taking nefazodone Association acknowledges that the literature (17.9% vs 8.3%). Patients taking imipramine differs as to whether patients taking SSRIs also had a greater increase in body weight beyond the acute phase experience weight gain than patients taking nefazodone in both as a medication side effect.19 Six-month place- short-term and long-term phases, indicating bo-controlled studies have found no significant that nefazodone may be less likely to cause difference in weight gain with fluoxetine15 or weight gain than both SSRIs and tricyclic term SSRI use
citalopram.17 A 12-month study of citalopram antidepressants when used longer than 1 year.
leads to weight
reported 4.7% of 541 patients with depressionexperienced weight gain of greater than 5 kg.20 gain is still
Another placebo-controlled study of the pro- phylactic effect of citalopram in unipolar, Bupropion is essentially devoid of antihista- recurrent depression at 48 to 77 weeks reported minic effects and is commonly associated with no weight gain with citalopram.21 weight loss. This aminoketone weakly blockspostsynaptic serotonin and norepinephrine Weight gain more likely
uptake, in addition to inhibiting presynaptic with long-term paroxetine
Fava et al22 presented data from a 6-month A number of studies have compared double-blind non–placebo-controlled study of bupropion with placebo, sertraline, tricyclic paroxetine, sertraline, and fluoxetine. The antidepressants, or trazodone.16,26–29 All rate of emergence of significant weight gain, showed that bupropion was associated with defined as a 7% or greater increase in body weight loss (mean 2.5 lb), whereas the other weight, was 25.5% for paroxetine vs 4.2% drugs were associated with weight gain. In with sertraline and 6.8% with fluoxetine.
placebo-controlled studies, depressed outpa- A 24-week double-blind study of paroxe- tients treated for 12 weeks lost, on average, 0.3 tine and sertraline23 showed significantly kg with fluoxetine,15 0.8 kg with sertraline16 or more weight gain with paroxetine but failed to 1.1 kg with bupropion.16 In a separate 52-week report the percentage of patients who exhibit- double-blind placebo-controlled study, Weihs ed at least a 7% change in weight, the accept- et al29 showed a mean weight loss of 1.2 kg in ed standard of clinical significance.
patients treated with bupropion.
ANTIDEPRESSANTS AND WEIGHT GAIN
DESHMUKH AND FRANCO
weight gain and may fall back into depression.
On the other hand, fighting weight gain once Through blockade of histamine H1 and sero- it has occurred can be very difficult, and it is tonin 2C receptors, mirtazapine is likely to be advisable to consider the likelihood and related to weight gain in both the short term potential consequences of weight gain when and the long term.1 A piperazine-azepine choosing an antidepressant.36,37 compound, it enhances central noradrenergic Educating the patient about the chances
and serotonergic activity. It is a potent antag- of weight gain as a side effect of treatment and onist of H1, serotonin 2, and serotonin 3, and its management is best accomplished through a moderate antagonist of peripheral alpha-1 a strong patient-physician alliance and is inte- adrenergic and muscarinic receptors.
gral to positive outcome.
A meta-analysis of four US studies found Preventing weight gain in patients on
that patients gained weight during the first 4 antidepressants is the ideal strategy. It typi- weeks of treatment.30 cally involves caloric restriction and Mirtazapine is more likely to cause weight increased caloric expenditure through aero- gain than placebo but may be less likely to bic exercise.1 Patients may benefit from a cause weight gain than tricyclic antidepres- nutritional consultation and participation in sants such as amitriptyline.31,32 A comparison a low-cost commercial weight-loss program.
of mirtazapine and venlafaxine in the treat- Individuals can be asked to record weekly ment of severely depressed hospitalized weights, and thus both clinician and patient patients with melancholic features identified a can be alerted to small increases in weight significant weight gain of 2.0 ± 3.7 kg in the before the problem becomes too difficult.
mirtazapine group and a loss of 0.5 ± 2.9 kg in Maintaining a food diary and behavioral the venlafaxine group.33 techniques such as increasing meal frequen-cy, smaller meals, or decreasing the pace of eating can help.
Switching to another drug with a lower
Venlafaxine, a potent inhibitor of serotonin risk of weight gain is an alternative approach, and norepinephrine reuptake, is sometimes although this carries a risk of loss of clinical gain with
prescribed for patients with psychomotor retardation, hypersomnia, or resistance to Addition of another agent such as a stim-
other antidepressants.34 ulant (methylphenidate, amphetamines), an A short-term study comparing venlafax- H2 receptor antagonist (famotidine), tri- ine with fluoxetine found no significant iodothyronine, topiramate, bupropion, or nal- weight gain with either agent.35 Thus, like trexone may help diminish weight gain.1,37 SSRIs and unlike mirtazapine, venlafaxine is Although none has been tested systematically, another drug
less likely to cause weight gain in the short low doses have been prescribed along with an term,33 although there are not enough data to antidepressant in an effort to avoid weight comment on its long-term effects.
gain associated with antidepressant therapy.
In our practice, we have found that adding ■ RECOMMENDATIONS FOR MANAGEMENT
low-dose bupropion (100 to 150 mg/day) ortopiramate (25 to 50 mg/day) may help weight Many patients prematurely discontinue their loss when used in addition to diet control and medication as a result of increased appetite or 1. Janicak PG, Davis JM, Preskorn SH, Ayd Fj Jr. Principles and Practice of
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ADDRESS: Kathleen Franco, MD, Section of Consultation-Liaison Psychiatry,
23. Agren H, Aberg-Wistedt A, Akerblad AC, et al. Sertraline vs paroxe-
Department of Psychiatry and Psychology, P57, The Cleveland Clinic tine in major depression: a multicenter double blind 24 week compari- Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. INTERNAL Clinical vignettes and questions on the
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