Brooke Parish, MD
University of New Mexico
In 2002, 8.5% of the US population purchased at least one prescription antidepressant.1 Given this relatively high rate of antidepressant use, best practices should be followed in choosing the correct medication and dosing, to avoid adverse events or ineffective treatment.
Two of the major classes of antidepressants that are more commonly prescribed are the selective serotonin reuptake inhibitors (SSRIs) and the tricyclic antidepressants (TCAs). The SSRIs are generally the antidepressants of first choice. They are relatively safe and effective. The Cochrane Collaboration reviewed 32 well-conducted trials and found SSRIs to be just as effective as TCAs with fewer adverse effects in the elderly population.2 In the inpatient population, TCAs appear to be slightly more effective than SSRIs, but TCAs were noted to have decreased tolerability.3 Given the popularity and tolerability of SSRIs, this review focuses mainly on this group of antidepressants and also touches on some of the newer unique antidepressants.
ADVERSE EFFECT PROFILE OF ANTIDEPRESSANTS
Most medications in the SSRI class are well tolerated. The 2 most frequently reported adverse effects are gastrointestinal distress and sexual adverse effects. Gastrointestinal distress can be seen at the beginning of therapy and with dose increases, but over time this category of adverse effects tends to decrease. On the other hand, sexual dysfunction due to the blockade of specific serotonin receptors (the common mechanism of action of most of the drugs in this class of antidepressants), namely the 5-HT1b, 5-HT2a, and 5-HT2c receptors, is of particular concern for the long-term compliance with these antidepressant medications for patients. This concern is exacerbated by an already high underlying prevalence of sexual dysfunction in patients with depression. Authors have estimated that 30-70% of patients with depression have sexual dysfunction that can be attributed to various causes, including the depression itself, other related medical or psychiatric conditions, or deterioration of social relationships.4
Patients taking bupropion have been reported to experience the least amount of sexual dysfunction compared to other commonly used antidepressants, with 22-25% of patients still reporting difficulties compared to rates in the 40% range for other medications especially in the SSRI class.4 Strategies for addressing sexual dysfunction may include augmentation with bupropion, drug holidays, decreasing dose, changing medications, adding medications intended to treat erectile dysfunction, and waiting for tolerance.
Other common adverse effects are pronounced in specific medications. Citalopram, for example has the greatest risk of somnolence, weight gain, memory impairment, and sexual dysfunction. This is secondary to citalopram’s affinity for histamine receptors.5 Paroxetine has the greatest risk of anticholinergic adverse effects, which may include dry mouth, constipation, dizziness, tachycardia, blurred vision, and urinary retention. A recent adverse effect that has come to light with SSRIs is an increase in bleeding risk, mainly upper gastrointestinal bleeding. Those at highest risk are the elderly and those who have had previous gastrointestinal bleeding.6
Another common adverse effect seen with SSRIs and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) is discontinuation syndrome, which occurs when the medication is stopped suddenly and consists of symptoms such as gastrointestinal distress, influenza-like symptoms, sensory disturbances (eg, electric shocks), and psychological symptoms of depressed mood and anxiety. Of all the SSRIs and SSNRIs, discontinuation syndrome is most frequently reported with paroxetine and venlafaxine. Many authors believe this adverse effect is secondary to the shorter half-life of these medications. However, multiple cases of discontinuation syndrome have also been reported with fluoxetine. In the case of fluoxetine, the discontinuation syndrome appears to be delayed, which may be a result of the medication’s longer half-life. Discontinuation syndrome has also been noted in neonates whose mothers have been taking SSRIs or SSNRIs.
Sleep can also be affected by antidepressants. As a general rule, SSRIs tend to have alerting effects and decrease sleep efficiency. Bupropion also can cause sleep disturbances. However, the newer antidepressant mirtazapine can increase sleep efficiency.
Mirtazapine, a noradrenergic and serotonergic antidepressant, has a unique tolerability and adverse-effect profile. On the positive side, multiple studies suggest that sexual dysfunction may be lower with mirtazapine than with SSRIs or SSNRIs. However, the main adverse effect with mirtazapine is weight gain. This adverse event may be overstated; one long-term study showed only an average gain of 3.3 kg with mirtazapine compared to a 2.7 kg weight gain with placebo.7 That said, SSRIs have also been implemented in weight gain during long-term therapy.
SAFETY OF ANTIDEPRESSANTS
The role antidepressants have in self-harming behaviors is both complex and controversial. Antidepressants now carry a black box warning from the US Food and Drug Administration (FDA) for use in children, adolescents, and young adults. Yet, multiple epidemiological studies suggest that antidepressants can decrease suicide and suicidal behavior. One study found that the rate of teenage suicide rose as the number of prescriptions fell.8 While associations are not causations, certainly this new research points to the need for more clarification. Appropriate medication therapy should not be withheld from younger patients, but appropriate consent should be obtained following a detailed discussion of risks and benefits. In the cases of mild depression, psychotherapy and other modalities should be tried first.
Until recently, monoamine oxidase inhibitors (MAOIs) have generally fallen out of favor with practitioners given their dietary restrictions and drug interactions. However, the selegiline transdermal system has decreased some of these risks; at the lowest dose, the MAOI diet does not need to be followed with this therapy.9
Generally, SSRIs are relatively safe in overdose, which is in sharp contrast to TCAs. Nevertheless, at least a theoretical risk remains of cardiotoxicity secondary to active metabolites. For example, citalopram has an active metabolite, didesmethylcitalopram, which can prolong the QT interval.
Limited research regarding the safety of mirtazapine overdose exists, although overdose deaths have been reported when mirtazapine is used in combination with TCAs. Furthermore, rare cases of bone-marrow suppression have been reported with mirtazapine.10
Duloxetine was approved by the FDA in 2004. Duloxetine is an SSNRI that shows equal serotonin and norepinephrine reuptake inhibition at all doses. Both of the SSNRIs venlafaxine and duloxetine increase blood pressure, and, at least in the case of venlafaxine, hypertensive crisis has been reported.5 While all antidepressants (with the possible exception of escitalopram) have case reports of hepatotoxicity, this risk is slightly greater with duloxetine.
DOSING OF ANTIDEPRESSANTS
The goal in prescribing antidepressants is to quickly relieve symptoms at the lowest possible dose and with a minimum of adverse effects. As a general rule, to minimize the chance of dose-dependent adverse effects, the prescribing physician should start with the lowest effective dose and then titrate upward until the therapeutic goals are achieved. This strategy is especially important with certain classes of antidepressants that have significant adverse effects, such as the TCAs. However, a strategy of titration is not without risk; an unduly slow titration can cause a delay in reaching therapeutic effectiveness and can increase the risk of patient discontinuation for other reasons (ie, if the medication is determined to be ineffective by the patient). Note that many antidepressants are available in lower doses to help with titration and that lower doses may also be necessary in the case of concomitant medical illness.
Citalopram’s efficacy can start at 20 mg, but, generally, 40 mg per day is the effective dosage, and it can be titrated up to 60 mg per day. Patient with more severe symptoms will generally require higher doses. Fluoxetine has similar dosing guidelines. As a general rule, the maximum recommended dosage of paroxetine is 50 mg per day, though many patients respond with dosages as low as 20 mg per day. The lowest effective dosage for sertraline is 50 mg per day, and the maximum daily dose is 200 mg. The reference dose of duloxetine is 60 mg daily, but acceptable dosages range from 40-120 mg per day.11 While duloxetine is generally well tolerated, adverse events such as gastrointestinal distress tend to cause a higher discontinuation rate in comparison to other antidepressants. For this reason, duloxetine can be started at a dose as low as 30 mg and titrated. For venlafaxine, a “standard” dose is approximately 150 mg and “high” dose is 300 mg a day.7 Venlafaxine is generally given in the extended-release formulation and not the immediate-release formulation for dosing convenience and to minimize the risk of gastrointestinal side effects.
The treatment of depression continues to evolve, with an increasing number of treatment options available. Even as medication choices increase, physicians should keep in mind that all medications carry risks that must be weighed against the risk of not treating symptoms.
REFERENCES
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Mottram P, Wilson K, Strobl J. Antidepressants for depressed elderly. Cochrane Database Syst Rev. 2006;(1):CD003491.
Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58(1):19-36.
Ginzburg R, Wong Y, Fader JS. Effect of bupropion on sexual dysfunction. Ann Pharmacother. 2005;39(12):2096-9.
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Thase ME, Nierenberg AA, Keller MB. Mirtazapine in relapse prevention: a double-blind placebo-controlled study in depressed outpatients. Eur Neuropsychopharmacol. 2000;10(suppl 3):S265-6.
Dyer O. Teen suicide rate rises as prescribing of SSRIs falls, study finds. BMJ. 2007;335(7619):531.
Azzaro AJ, Ziemniac J, Kemper E, Campbell BJ, VanDenBerg C. Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6mg/24h): a comparison with oral selegiline capsules. J Clin Pharmacol. 2007;47(10):1256-67.
Ozcanli T, Unsalver B, Ozdemir S, Ozmen M. Sertraline- and mirtazapine-induced severe neutropenia. Am J Psychiatry. 2005;162(7):1386.
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