Depression Symptoms Treatment

Major depression affects 5% to 10% of patients seen by primary care physicians. Despite the advent of new antidepressant drugs, up to 20% of patients remain fully resistant to treatment and a further 20% to 30% only partly respond to treatment. Therapy should aim at eradicating depressive symptoms completely (i.e., complete remission) because incomplete recovery is associated with continued functional impairment and a greater risk of relapsing to full-blown depression. One way to approach treatment of major depression is through the mnemonic, OSCAR, which highlights the five steps for treating depressed patients: Optimization, Substitution, Combination, Augmentation, and Review. While optimization is always the first step, there is no clear consensus on what the next step should be if optimization fails.

Quality of evidence

Relevant articles were identified by MEDLINE search from 1966 to January 1999. MeSH headings included depression, combination, augmentation, lithium, triiodothyronine, pindolol, buspirone, methylphenidate, and electroconvulsive therapy (ECT). The search was limited to English-language articles on human subjects aged 18 years and older appearing in well-recognized, peer-reviewed medical journals. Studies were critically reviewed, references from papers retrieved were scrutinized for other relevant reports, and all were combined with studies in the author’s personal files.

Article selection was based on clinical relevance and study design. The recommendations of the Canadian Network for Mood and Anxiety Treatment, the clinical practice guidelines of the United States Department of Health, and product monographs of antidepressants were analyzed.

Optimization

Optimization is prescribing an antidepressant in the best possible way. Optimization of dose (must be adequate) and length of time a patient remains on the adequate dose are important. Optimization includes encouraging compliance, which improves when patients are educated about their illnesses and medications. Optimization includes attention to psychosocial stressors that might contribute to the illness. The effect of the illness on a spouse, children, friends, and employment should be addressed.

Before prescribing any antidepressant, accurate diagnosis is essential. Depressive symptoms can occur in conditions other than major depression (e.g., alcohol abuse) and might be secondary to medical conditions or medications.

First-line antidepressants. Antidepressants are classified according to their presumed mechanisms of action (Table 1). Each antidepressant affects one or more of three neurotransmitters: serotonin (5-hydroxytryptamine [5HT]), norepinephrine (NE), and dopamine (DA). No compelling data indicate that one antidepressant is more effective than another, and choice depends on other issues, such as tolerability, safety in overdose, interaction with other drugs, and cost. When depression is severe, however, antidepressants affecting both serotonin and norepinephrine (eg, tricyclics [TCAs], venlafaxine) might be more effective at relieving symptoms.

Table 1. Antidepressants classified according to their presumed mechanism of action
MECHANISM OF ACTION
5-hydroxytriptamine (5HT) and norepinephrine (NE) reuptake inhibition (with effects on multiple receptors)	Tricyclic antidepressants: desipramine, nortriptyline
5HT and NE reuptake inhibition	Serotonin norepinephrine reuptake inhibitor: venlafaxine
5HT reuptake inhibition	Selective serotonin reuptake inhibitors: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram
NE and dopamine reuptake inhibition	Bupropion
5HT-2 antagonism and 5HT reuptake inhibition	Serotonin antagonist reuptake inhibitors: nefazodone, trazodone
NE reuptake inhibition	Reboxetine
Monoamine oxidase (MAO) inhibition • Irreversible MAO inhibitors • Reversible MAO-A inhibitor	Phenelzine, tranylcypromine Moclobemide

Dosing strategies.Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, paroxetine, citalo-pram, and fluoxetine, are usually initiated at doses that are ultimately the usual therapeutic doses (i.e., 50, 20, 20, and 20 mg/d, respectively). Fluvoxamine is started at 50 mg/d for the first week (to reduce nausea) and then increased to 100 mg/d, its usual therapeutic dose. When depression is associated with marked anxiety, SSRIs are initiated at a lower dose to prevent early worsening of anxiety symptoms. Some patients metabolize SSRIs quickly and, therefore, when they do not respond after 4 weeks, dose should be increased. The new dose should be continued for at least 1 week before increasing further. Usual maximum dose for fluoxetine, citalo-pram, and paroxetine is 60 mg/d, for sertraline is 200 mg/d, and for fluvoxamine is 300 mg/d.

Tricyclics are started at 50 mg/d with dose increased every third day until 150 mg/d is reached. If there is no response by 4 weeks, dose should be increased by 50 mg/d every 5 days until response occurs or side effects intervene. The usual maximum dose for TCAs is 300 mg/d. Nortriptyline is an exception because it loses its efficacy when doses exceed 100 mg/d.

Nefazodone is most effective when prescribed in doses of 300 to 500 mg/d. Nefazodone is initiated at 50 mg bid so patients can become accustomed to the medication; nefazodone is usually given twice daily because of its short half-life (3 hours).

Monoamine oxidase inhibitors (MAOIs) require a tyramine-free diet and the risk of interaction with other drugs demands caution. The usual therapeutic dose range for phenelzine is 45 to 90 mg/d; the range for tranylcypromine is 20 to 60 mg/d. With half-lives of 2 hours, MAOIs are given in divided doses.

Moclobemide does not inactivate the enzyme that metabolizes tyramine and, thus, there are no dietary restrictions. The therapeutic dose of moclobemide is 450 to 600 mg/d; the drug is usually given twice daily because of its half-life of 1 hour. Starting dose is 150 mg morning and evening with gradual increase to a maximum of 600 mg/d.

Venlafaxine extended release is commenced at 75 mg/d, although patients sensitive to side effects might benefit from a 37.5 mg/d dose for 4 to 7 days before increasing to 75 mg/d, the usual effective dosage for mild to moderately depressed outpatients. There is a significant relationship between increasing dose and increasing efficacy. If response is incomplete by 4 to 6 weeks, the dose may be increased incrementally to a maximum of 225 mg/d. Increases should occur no more frequently than every 1 to 2 weeks, increasing by 37.5mg to 75mg on each occasion.

Bupropion sustained release is initiated at 100 to 150 mg once daily in the morning, increasing to a maximum of 300 mg/d if response is poor. Doses greater than 150 mg/d should be given bid, preferably with at least 8 hours between doses.

Adequate duration of an antidepressant trial. Once dose has been optimized, it is important that patients remain on the adequate dose for sufficient time. A trial should last at least 6 weeks because it usually takes 4 to 6 weeks before response to an anti-depressant occurs. If a patient does not respond at all by week 6, or if the response is only partial, diagnosis, medication dose, and compliance should all be reviewed and other treatment options considered.

Drugs

Imipramine (Tofranil)

Desipramine (Norpramin)

Nortriptyline (Avertyl)

Venlafaxine (Effexor)

Fluoxetine (Prozac)

Fluvoxamine (Luvox)

Paroxetine (Paxil)

Sertraline (Zoloft)

Citalopram (Celexa)

Bupropion (Welibutrin)

Nefazodone (Serzone)

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Moclobemide (Manerix)

Reboxetine (Edronax, Vestra)

Triiodothyronine (Cytomel)

Pindolol (Visken)

Buspirone (Buspar)

Methylphenidate (Ritalin)

Substitution

Substitution (or switching) is replacing an ineffective drug with a new drug. Switching to a new agent keeps things simple and avoids potential drug-drug interactions. Monotherapy might also be associated with greater compliance.

Controlled studies have shown that when patients are switched from one TCA to another TCA (i.e., to an antidepressant of the same class) the response rate is only 10% to 30%. When double-blind studies examined patients’ switching to different classes of antidepres-sants (e.g., SSRI to TCA), however, response rates were higher at 40% to 70%.

Open-label studies suggest that when patients fail to respond to one SSRI they might respond to a different SSRI. The value of switching from one SSRI to another, however, is controversial, and further studies are needed to determine the effectiveness of this strategy.

Most antidepressants can be switched quickly but, even when no washout period is required, good clinical practice recommends tapering and stopping one antidepressant before starting the next medication. In situations where time is important, the next medication can usually be started and increased while tapering the old medication. Rapid switching minimizes the time required to obtain relief from depressive symptoms.

When switching from an MAOI to any other drug, a washout period of 2 weeks is required; when switching from moclobemide, a washout period of 3 days is recommended. When switching to an MAOI or moclobemide from any other drug, a washout period of 1 week (5 weeks for fluoxetine) is required.

Some SSRIs elevate TCA levels by inhibiting enzymes that metabolize TCAs. When switching from an SSRI to a TCA, introduce the TCA at a lower dose. Similarly, before switching to an SSRI, it is wise to reduce the dose of a TCA

Combination

Combination is the prescription of two antidepressants, each from a different therapeutic class and each, supposedly, with its own unique mechanism of action. It is assumed that the unique effects of each drug will cumulatively interact to provide a greater therapeutic effect than either drug alone.

One study reported a 65% response rate when patients poorly responsive to fluoxetine had a low-dose TCA added to fluoxetine. In a similar open retrospective trial, an SSRI-TCA combination yielded a 35% response rate. In a double-blind study, only 25% of patients resistant to treatment with fluoxetine responded when low-dose desipramine was added. Further controlled studies are needed to clarify the effectiveness and usefulness of this strategy. The SSRI-TCA combinations are potentially dangerous due to the ability of SSRIs to increase TCA plasma levels, and TCA levels must be monitored in these situations.

Novel antidepressant combinations include SSRIs and moclobemide and SSRIs and bupropion. Such combinations should be prescribed by physicians with expertise in psychopharmacology.

Augmentation

Augmentation is addition of an agent to boost or magnify the effects of the original antidepressant. The new agent is not considered an antidepressant when used alone. Augmentation might be preferred by patients who have had some degree of response to an antidepressant and who are reluctant to risk losing this improvement. Augmentation might also work more quickly than switching.

Lithium.Almost all placebo-controlled studies found lithium to be more effective than placebo; response to lithium was about 50%. Although most of the original studies were done with TCAs, more recent placebo-controlled studies demonstrate that lithium augmentation is also effective with SSRIs.

The efficacy of lithium augmentation appears to depend on achieving adequate serum lithium levels (0.4 to 1.0 mEq/L) and a dose of 900 mg/d is usually required. Lithium augmentation of fluoxetine can produce marked gastrointestinal adverse effects, and lithium should, therefore, be initiated at a low dose when augmenting SSRIs. Lithium augmentation should be continued for 6 weeks before deciding that treatment is ineffective.

Thyroid hormone. In several, but not all, open and controlled studies, T3 (triiodothyronine) augmented the response to TCAs, with positive studies reporting a success rate of up to 50%. In one report, T3 successfully augmented the responses of three patients receiving fluoxetine. For augmentation, the usual dose of T3 is 25µg/d. When effective, T3 acts within 2 to 4 weeks.

Pindolol. Following administration of SSRIs, the concentration of serotonin (5HT) in the synaptic cleft increases. This results in stimulation of presynaptic receptors that causes a decrease in 5HT release through negative feedback. Pindolol blocks these receptors and might augment antidepressant activity by inhibiting negative feedback. Several open-label studies support this theory, but only three of six randomized controlled trials clearly demonstrate benefits from addition of pindolol to an SSRI. Further investigation is required.

Buspirone. Several open-label studies suggest that buspirone (20 to 50 mg/d) is effective in augmenting the antidepressant effects of SSRIs. The only placebo-controlled study, however, found no difference between buspirone and placebo.20 In that study, the placebo response was particularly high (46.7%), and further studies are required to reliably determine buspirone’s efficacy as an augmentor of SSRIs.

Stimulants. There are no controlled studies examining the role of stimulants as augmenting agents. In a recent open trial, methylphenidate successfully augmented all of five patients with poor response to SSRIs. Further studies are required.

Electroconvulsive therapy. For patients who fail to respond to adequate trials of antidepressants, the response rate to ECT is approximately 50%. Unfortunately, 60% of these ECT responders relapse within 1 year, usually within the first 4 months.

L-tryptophan. Controlled studies confirm the ability of tryptophan (the precursor of 5HT) to augment the antidepressant effects of MAOIs, but the risk of toxic interaction makes this strategy hazardous. There is insufficient evidence in support of tryptophan’s capacity to enhance the efficacy of SSRIs or TCAs.

Psychotherapy. The pharmacological treatment of depression usually occurs in the context of a psychotherapeutic relationship. When a patient is not responding, reconsider psychotherapeutic strategies. Cognitive therapy might improve the response of patients resistant to treatment with antidepressant medication alone.

Review (and referral)

When response remains poor despite some of the strategies described above, the steps taken should be reviewed, including reassessing the diagnosis and the possibility of comorbid conditions. Referral to a psychiatrist is appropriate when treatment fails or when diagnosis is unclear. Referral should be made on an urgent basis when a patient becomes suicidal or psychotic.

Key points

• The mnemonic OSCAR refers to five steps for treating depressed patients: optimization, substitution, combination, augmentation, and review.

• Optimization means choosing an appropriate antidepressant, building to the correct dose, and allowing sufficient time for it to work.

• Substitution is replacing an ineffective drug with a new one.

• Combination is usually of two antidepressants from different therapeutic classes (e.g., selective serotonin reuptake inhibitors and tricyclic antidepressants) and should be approached cautiously.

• Augmentation adds an agent, such as lithium, thyroid hormone, pindolol, buspirone, or electroconvulsive therapy, to boost the effect of an antidepressant.

• When all else fails, review the case and consider referral.

Résumé

(French Language)

Objectif

Examiner la pharmacothérapie contre la dépression et évaluer les stratégies de traitement actuelles en vue de tirer profit au maximum des avantages des médicaments antidépresseurs.

Qualité Des Données

Une recension dans MEDLINE a été effectuée jusqu’à janvier 1999 à l’aide des rubriques en anglais pour dépression, combinaison, augmentation, lithium, triiodothyronine, pindolol, buspirone, méthylphénidate et électrochoc, pour trouver des essais aléatoires contrôlés, des aperçus systématiques et des rapports de consensus. Des études récentes de grande qualité ont souvent été relevées. Les références citées dans les articles retenus ont fait l’objet d’un examen pour trouver d’autres rapports pertinents. La préférence a été accordée aux articles plus récents et aux études bien conçues. Les recommandations de groupes scientifiques ont été analysées.

Principal Message

La pharmacothérapie contre la dépression repose sur l’optimisation de la thérapie antidépressive. Lorsque les symptômes persistent malgré l’optimisation, figurent au nombre des autres stratégies possibles la substitution, la combinaison, l’augmentation, la révision et parfois l’aiguillage. Les décisions se fondent sur les données probantes à l’appui des diverses stratégies.

Conclusions

Les antidépresseurs ne fonctionnent que lorsqu’ils sont prescrits correctement. Une sensibilisation aux stratégies d’utilisation des antidépresseurs et d’évaluation de leur efficacité rehausse la capacité des médecins de première ligne de traiter cette affection courante.

Points de repère

• Le sigle mnémonique OSCAR représente les cinq étapes du traitement des patients dépressifs: l’optimisation, la substitution, la combinaison, l’augmentation et la révision.

• L’optimisation signifie choisir l’antidépresseur approprié et la dose correcte, et accorder suffisamment de temps pour permettre à l’agent de fonctionner.

• La substitution consiste à remplacer un médicament inefficace par un nouveau.

• La combinaison se traduit habituellement par le recours à deux antidépresseurs de classes thérapeutiques différentes (p. ex. certains inhibiteurs du recaptage de la sérotonine et les antidépresseurs imipraminiques) et elle devrait être adoptée avec prudence.

• L’augmentation veut dire l’ajout d’un agent, comme le lithium, l’hormone thyroïdienne, le pindolol, le buspirone ou l’électrochoc, pour amplifier l’effet de l’antidépresseur.

• Quand tout le reste a échoué, il faut revoir le cas et examiner la possibilité d’un aiguillage.