Pharmacological Management of Major Depressive Disorder

November 11, 2007

{mosimage}Kannayiram Alagiakrishnan, MD
University of Alberta

{mosimage}Cheryl Sadowski, BSc (Pharm), PharmD
University of Alberta 

About 121 million people worldwide suffer from depression. Major depression is one of the main causes of disability adjusted life years (DALY) as measured by the global burden of disease.1 The lifetime risk of major depression is about 15% for men and about 30% for women.2 Numerous types of depression exist, such as melancholic, atypical, psychotic, postpartum, bipolar, resistant, and mixed depression.3 The most commonly encountered types of depression and specific recommendations for their pharmacologic management are discussed below.

Many medications are used for the management of major depression. These include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), second generation atypical antidepressants (eg, bupropion, mirtazapine), psychostimulants (eg, methylphenidate), mood stabilizers (eg, lithium), and augmentation drugs (eg, triiodothyronine). Antidepressants work through a variety of mechanisms, a topic beyond the scope of this newsletter, but generally influence the function of neurotrasmitters such as norepinephrine, serotonin, or dopamine by exerting an impact on the interaction of these neurotransmitters with their receptors.

The management of depression begins in building a partnership with patients by explaining that antidepressants are not addictive and that patients should not expect immediate results with antidepressants. Ensuring realistic expectations is necessary for patient compliance. A team approach is also necessary. Physicians must work closely with pharmacists, psychologists, nurses, and other therapists to optimize outcomes in depression. In fact, responses may be variable with antidepressants. With the first trial of antidepressant therapy, approximately 19-34% of patients do not respond and 12-15% exhibit partial response.4 Physicians should emphasize that the first trial of antidepressant therapy should be maintained for at least 3-6 months. At the termination of antidepressant treatment, the medication should be gradually tapered over several weeks.

Melancholic depression
Melancholic depression presents as loss of pleasure in activities and as vegetative symptoms such as exacerbation of depression in the morning, early-morning awakening, and significant weight loss. Some evidence indicates that TCAs and venlafaxine may be more effective than SSRIs in patients with this type of depression.5, 6

Atypical depression

Patients with atypical depression have hyperphagia, hypersomnia, marked fatigue of extremities (leaden paralysis), and increased rate of body dysmorphic disorder. The definition of atypical depression as found in the text revision of the 4th edition of the Diagnostic and Statistics Manual of Mental Disorders (DSM-IV-TR) requires that patients must have at least 2 of 4 clinical features.7 MAOIs may be more effective than TCAs and SSRIs in treating atypical depression.8 However, in view of the inconvenience and safety risks caused by dietary and other restrictions when using MAOIs, SSRIs may be considered a first-line class of medication for atypical depression.9 The current standard treatment for atypical depression includes SSRIs, bupropion, and reversible inhibitors of monoamine oxidase (RIMAs), such as moclobemide.10

Late-life depression

Features of late-life depression may include apathy, declining cognition with depression (ie, pseudodementia), depression with executive dysfunction syndrome, and psychotic features with depression.11 In older adults, TCAs have numerous adverse effects, like orthostatic hypotension, which can result in falls and cardiotoxicity. Most clinicians prefer to use the newer SSRIs, which have fewer serious adverse effects. SSRIs and SNRIs are the antidepressants of choice, followed by bupropion and mirtazapine.12 Challenges for the effective use of antidepressant medications in older adults, who often have complicated medication regimens, include increased risk for adverse effects and medication interactions, and nonadherence in many older adults.13
 Psychotic depression

Approximately 20% of patients hospitalized for depression may have psychotic depression.14 Patients with psychotic depression have hallucinations or delusions in addition to depressive symptoms. People with psychotic depression are usually aware that such hallucinations and delusions are not true. Only 20% of patients with this type of depression respond to antidepressant monotherapy.15 Most authorities suggest that an antipsychotic agent must be used in addition to an antidepressant in order to achieve a response.16 The ideal management includes a combination of an antidepressant and an atypical antipsychotic, if electroconvulsive therapy (ECT) therapy is not used. Novel therapies with antiglucocorticoids are used in the treatment of psychotic depression. Depression has been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Increased HPA-axis activity with elevated cortisol levels are found in psychotic depression.17 Studies with mifepristone, which is an antagonist of glucocorticoid receptors at higher doses, have reported it to be effective in the management of psychotic depression.18, 19

Postpartum depression

Postpartum depression (PPD) is quite common, with the overall prevalence estimated to be 13%.20 PPD is a severe condition that affects not only the woman suffering from the condition, but her entire family.21 As per the DSM-IV-TR, diagnosis of PPD requires a major depressive episode within the first 4 weeks after delivery. Treatment of PPD is challenging because of the paucity of research and the complicating factor of breastfeeding. Numerous pharmacotherapeutic agents have been studied, including hormone therapy (ie, estrogen and progestin), venlafaxine, and SSRIs (including fluoxetine, sertraline, and fluvoxamine).22 SSRIs are currently considered first-line therapy because of their demonstrated efficacy, tolerability, and safety. However, physicians must monitor the mother and infant for adverse effects. Symptoms of excess SSRI in the infant include irritability, GI upset, sedation, agitation, and poor feeding.23

Treatment-resistant depression
In patients diagnosed with depression, 30-45% of patients experience a partial response or no response to the first trial of antidepressant therapy.4 Although the response rate to antidepressants is low, a patient with poor or no response to antidepressants should be investigated for alcohol or substance abuse, undiagnosed hypothyroidism, inadequate antidepressant drug dose and duration, and nonadherence to treatment.24 Augmentation is one of the many strategies used to combat treatment-resistant depression. Meta-analysis and other systematic reviews have shown that lithium, methylphenidate, atypical antipsychotics, and triiodothyronine, when added to an antidepressant regimen, improve outcomes for patients with depression.25-28

Bipolar depression
Patients with bipolar depression type I have features of major depressive disorder and a history of one manic episode or a mixed episode. Patients with bipolar depression type II have more atypical symptoms (eg, hypersomnia, overeating) and hypomanic symptoms, including psychomotor agitation.29 When patients have depressive and manic features, they should be treated with a combination of a mood stabilizer (eg, lithium) and an antidepressant.30 Antidepressants used as monotherapy have the potential to induce mania in patients with bipolar disorder.31

Numerous natural health products, such as St. John’s Wort, tryptophan, 5-hydroxytryptophan, and others, have been used to treat depression. Of these products, St. John’s Wort has been studied most extensively. While numerous studies have been published, a recent Cochrane review examined 37 trials, finding the effects of St. John’s Wort to be slightly better than those of placebo and similar to those of SSRIs. However, the authors note that the trials displayed significant heterogeneity.32 The role for natural health products in the treatment of depression is reserved for patients who refuse conventional medication or whose depression levels are only mild to moderate. These products cannot be recommended as first-line agents.33

Depression is a complex disease and is, therefore, challenging to treat. Patients are heterogeneous in age at onset of disease, number and type of symptoms, comorbid conditions, and treatment response. All antidepressant drugs are effective, but certain classes of medications work best for specific types of depression. In fact, responses to the different classes of antidepressants may vary among patients, depending on their specific type of depression.

World Health Organization. Mental health: depression. Available at Accessed on October 7, 2007.

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Clerc GE, Ruimy P, Verdeau-Palles J. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. The Venlafaxine French Inpatient Study Group. Int Clin Psychopharmacol. 1994;9(3):139-43.

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Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression. Arch Gen Psychiatry. 1988;45(2):129-37.

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Søgaard J, Lane R, Latimer P, et al. A 12-week study comparing moclobemide and sertaline in the treatment of outpatients with atypical depression. J Psycho Pharmacol. 1999;13(4):406-14.

Alexopoulos GS. Depression in the elderly. Lancet. 2005;365(9475):1961-70.

Alexopoulos GS, Katz IR, Reynolds CF, Carpenter D, Docherty JP. The expert consensus guideline series: pharmacotherapy of depressive disorders in older patient. Postgrad Med. 2001;Special Report:1-86.

Zisook S, Downs NS. Diagnosis and treatment of depression in late life. J Clin Psychiatry. 1998;59(suppl 4):80-91.

Rothschild AJ, Mulsant BH, Meyers BS, Flint AJ. Challenges in differentiating and diagnosing psychotic depression. Psychiatr Ann. 2006;36(1):40-6.

Charney DS, Nelson JC. Delusional and nondelusional unipolar depression: further evidence for distinct subtypes. Am J Psychiatry. 1981;138(3):328-33.

Rothschild AJ. Challenges in the treatment of depression with psychotic features. Biol Psychiatry. 2003;53(8):680-90.

Keller J, Flores B, Gomez RG, et al. Cortisol circadian rhythm alterations in psychotic major depression. Biol Psychiatry. 2006;60(3):275-81.

Belanoff JK, Rothschild AJ, Cassidy F, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry. 2002;52(5):386-92.

Flores BH, Kenna H, Keller J, Solvason HB, Schatzberg AF. Clinical and biological effects of mifepristone treatment for psychotic depression. Neuropsychopharmacology. 2006;31(3):628-36.

O’Hara MW, Swain AM. Rates and risk of postpartum depression: A meta-analysis. Int Rev of Psychiatry. 1996;8:37-54.

Horowitz JA, Goodman JH. Identifying and treating postpartum depression. J Obstet Gynecol Neonatal Nurs. 2005;34(2):264-73.

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Kornstein SG, Schneider RK. Clinical features of treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 16):18-25.

Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-34.

Lavretsky H, Kim MD, Kumar A, Reynolds CF 3rd. Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. J Clin Psychiatry. 2003;64(12):1410-4.

Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. a meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-8.

Kennedy SH, Lam RW. Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics. Bipolar Disord. 2003;5(suppl 2):36-47.

Hantouche EG, Akiskal HS. Bipolar II vs unipolar depression: psychopathologic differentiation by dimensional measures. J Affect Disord. 2005;84(2-3):127-32.

Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biol Psychiatry. 2000;48(6):558-72.

Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry. 2001;62(4):249-55.

Linde K, Mulrow CD, Berner E, Egger M. St John's Wort for depression. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.:CD000448. COI: 10.1002/14651858.CD000448.pub2

Shaw K, Turner K, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002; 1:CD003198.

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