Major Depressive Disorders

Kiung Hsia Ling 2/09/09

Depression is a common, chronic, and

potentially debilitating illness that has tempered the human condition since the beginning of recorded history. Although many people experince “the blues” from time to time, the term depression is reserved in psychiatry to define a specific medical condition with distinctive biologic and pharmacologic implications

Onset occurs most commonly in the late 20s,

but there is a wide range and the first episode may actually present at any age. The observed peak onset in females is between 35 and 45 years of age and in males it occurs most commonly after age 55. Genetic factors may play a major role in the cause of depression. First degree relatives off depressed individuals are 2.7 times more likely to have depression if one parent is afflicted, and 3.0 times more likely if both parents suffer from depression.

1.

At least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning. One of the symptoms must be either depressed mood or loss of interest/pleasure         

1. 2.

Depressed mood most of the day, nearly every day Loss of interest in pleasurable activities most of the day, nearly every day Change in weight or appetite when not dieting Insomnia or hypersomnia nearly every day Fatigue or loss of energy nearly every day Diminished ability to think or concentrate, or indecisiveness Feelings of worthlessness or excessive or inappropriate guilt nearly every day Psychomotor agitation or retardation nearly every day Recurrent thoughts of death or suicidal ideation

Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning Symptoms are not caused by an underlying medical condition or substance (e.g. medicationsor recreational drugs)

1.

Cardiovascular agents    

1.

Central nervous system agents   

1.

Barbiturates Chloral hydrate Phenytoin

Hormonal agents   

1.

Beta-blockers Methyldopa Procainamide Reserpine

Corticosteroids Progestins Tamoxifen

Others    

Indomethacin Interferon Isotretinoin Mefloquine

Although pharmacologic intervention has

becomes the primary treatment modality for relieving depression symptoms, the efficacy and suitability of other therapeutic options should not be overlooked. A wider variety of other therapeutic interventions exist, including psychotherapy, ECT, light therapy, sleep deprivation, etc. .

 Is a safe, rapid-acting, and highly effective therapeutic intervention that

continues to suffer, ostensibly, from a poor public image.  Adjunctive medications are now routinely administered to prevent adverse effects and reduce morbidity (e.g. a short-acting barbiturate for general anesthesia, an anticholinergic agent to prevent bradycardia and dry excesssive airway secretions, and succinylcholine to prevent fractures from tonic-clonic contractions)  ECT features the induction of generalized seizures through an electric current delivered by bilateral or unilateral electrode placement.  Certain medications may raise seizure thresholds (benzodiazepines) or promote cognitive impairment (lithium) and should be discontinued before the procedure  ADR: are generally minimal and consist mainly of transient anterograde amnesia (difficulty remembering events around the time of the procedure), retrograde amnesia, confusion, headaches, and muscle aches. Cardiovascular effects (e.g. ventricular arrhythmias, MI are the most ominous sequelae, but these events are actuallyl quite rare)  Recommended for patients with treatment-resistant depression, severe vegetative depression, psychotic depression, and depression in pregnancy.  Overall response rates are rather impressive, ranging from 70% to 90%, and ECT has the distinct advantage of inducing a therapeutic response within the first week or two of treatments.

Reduce the symptoms of acute depression,

facilitate the patient’s return to a premorbid level of functioning, and prevent further episodes of depression. Whether or not to hospitalize the patient is often the first decision that is made in consideration of the patient’s risk of suicide, physical state of health, social support system, and presence of a psychotic and/ or catatonic depression

 Studies have found that antidepressants are of equivalent

efficacy when administered in comparable doses.  Because one cannot predict which antidepressant will be the most effective in an individual patient, the initial choice is made empirically.  Factors: patient’s history of response, pharmacogenetics (history of familial antidepressant response), subtype of depression, patient’s concurrent medical history, potential for drug-drug interactions, adverse events profile, and drug cost.  Although the pathophysiology of major depression remains elusive, can select from multiple drug therapies with different mechanisms of action.  Failure to respond to one antidepressant class or one antidepressant drug within a class does not predict a failed response to another drug class or another drug within the class.

 At present, 22 medications have received FDA approval

for the treatment of depression. They can be grouped together into four catogories - SSRIs (selective serotonin reuptake inhibitors)  Fluoxetine (Prozac)  Sertraline (Zoloft)  Escitalopram (Lexapro)

- TCAs (tricyclic antidepressants)  Amitriptyline (Elavil)  Imipramine (Tofranil0

- Monoamine oxidase (MAO) inhibitors

 Phenelzine (Nardil)  Tranylcypromine(Parnate)

- Miscellaneous

 Venlafaxine (Effexor)  Mirtazapine (Remeron)

 A similar delayed pattern of therapeutics response has been

observed with all antidepressant medications  Traditionally, patients have been informed that approximately 4 to 6 weeks must elapse before they will experience any therapeutic benefit from medication.  The pattern of patient response can be genralized, with neurovegetative symptoms (e.g. altered sleep or appetite, decreased energy, excessive worrying and irritability often the first to subside.  The cognitive symptoms are slower to response, and 3 to 4 weeks or more may elapse before improvements are evident. These symptoms include excessive guilt or pessimism, poor concentration, hopelessness or sadness, and decreased libido  Thus, patient should be counseled concerning this anticipated delay in therapeutic response and advised that optimal improvement may take ≥4 weeks in order to prevent patient may stop the medication prematurely.

 According to the guidelines released by the Agency for Health Care

Policy Research (AHCPR), antidepressant treatment can be broken down into three stages  Acute treatment phase: 3 months  Continuation treatment phase: 4-9 months  Maintenance treatment phase: variable  Acute and continuation treatment recommended for all patients with major depressive disorder (i.e., minimal duration of treatment = 7 months)  Decision to prescribe maintenance treatment is based on the following: - number of previous episodes, severity of previous episodes, family history of depression, patient age (worse prognosis if elderly), response to antidepressant, persistence of environmental stressors  Indefinite maintenance treatment is recommended if any one of the following criteria are met. - 3 or more previous episodes (regardless of age) - 2 or more previous episodes and age older than 50 yr - 1 or m0re and age older than 60 yr

 Were the most popular class of medications used to treat

depression  The acquisition cost for TCAs is quite low, and there are some providers who continue to prefer this class of medication for the treatment of severe or melancholic depression  Also for other indication as well e.g. migraine prophylaxis and chronic pain  Unfortunately, TCAs possess a variety of ADRs, ranging from bothersome (dry mouth, sedation, constipation) to serious (cardiovascular effects), which often prevent patients from receiving therapeutic doses of medication  This relatively high side-effects burden can also discourage clinicians from prescribing TCAs for elderly patients or those with certain medical conditions (e.g. BPH, cardiac arrthymias, narrow-angle glaucoma, dementia)

 Anticholinergic effects: dry mouth, blurred vision, constipation,

and urinary retention. Although pt may develop tolerance to these effects, they may never disappear completely  Counseling: pts with dry mouth, may tend to drink excessive fluids to relieve discomfort. To minimize the inherent potential for weight gain, pts should be advised to avoid caloric beverages and drink water or dietetic fluids instead. Sugarless gum or hard candy is often recommended as well  Can be very sedating and are usually administered at bedtime to minimize functional impairment  Confusion or memory deficits also may occur and can be onerous in elderly pts. The secondary amines may be more tolerable in this regard  Cardiovascular function: is a legitimate and serious concern. Due to their quinidine-like properties on prolonging cardiac conduction through His-Purkinje system. This, in conjunction with positive chronotropic and adrenergic-blocking properties, can lead to re-entry arrhythmias  Orthostatic hypotension: most common, will lead to bone fractures, lacerations and even MI. Tertiary amines (imipramine) may cause more severe orthostatic hypotension than secondary

Numerous advantage over older compounds,

including a lower side-effect burden, safety in overddose, less dosage titration, once-daily administration, and patient adherence. Results of a meta-analysis concluded that, although the overall efficacy of the two antidepressants classes was comparable, primary care patients receiving an SSRI were much less likely to discontinue therapy prematurely because of to side effects Although SSRIs are more expensive than TCAs, this additional cost may be offset by enhanced medication adherence rates and decreased relapse rates

 GI complaints: nausea, but this tends to be a transient

effect that diminishes after the first weeks or so of treatment. Typically, can cause some local GI irritation 1 or 2 hours after oral administration. Thus, pts should be advised to take the medication after a meal or snack  Diarrhea: 15-20%. Fortunately, often remits after 1 weeks of so of continued therapy and rarely requires an interruption of treatment.  Myriad effects on CNS: disturbances in sleep of disposition being a primary concern, have significant effects on sleep architecture and may prolong the REM stage, resulting in less fitful sleep. It should be emphasized that this is usually a transient phenomenon that occurs during the first week or two of treatment; sleep may actually improve from baseline once the antidepressants properties of the medication emerge.

Studies in melancholic depression and treatment-

resistant depression Common ADRs: nausea, constipation, somnolence, dry mouth, dizziness, nervousness, sweating, asthenia, abnormal ejaculation, and anorexia. Dose related May cause a dose-related increase in diastolic blood pressure, and baseline blood pressure is not a useful predictor of the occurrence of this phenomenon. BP should be monitored regularly during therapy, and dosage reduction or discontinuation may be necessary if sustained hypertension occurs

Modulating serotonin and norepinephrine

activity through a complex MOA In a comparative randomized trial with fluoxetine for moderate to severe depression, mirtazapine appeared to be much effective than the SSRI after 4 weeks of treatment, but the differences were no longer significant at 6 weeks. Common ADRs: sedation and weight gain

Drug

Brand Name Starting Dose (mg/day)

Maximum Dosage (mg/day)

Usual Dosage (mg/day)

Fluoxetine

Prozac

10

80

10-20mg OD

Sertraline

Zoloft

25

200

50mg OD

Escitalopram

Lexapro

5

20

10mg OD

Amitriptyline

Elavil

50

300

100-300mg OD

Imipramine

Tofranil

50

300

100-300mg OD

Venlafaxine XR Effexor XR

37.5

225

150mg OD

Mirtazapine

15

45

15-30mg ON

Remeron

 Depression is NOT a personality flaw or a weakness of

character  All antidepressants are equally effective (approximately 65% of pts receiving a therapeutic trial of any antidepressant medication will have a beneficial response)  Most pts receiving antidepressants will experience some side effects initially  Antidepressants should be taken at the same time daily  The response to antidepressants is delayed (several weeks may pass before begin to feel better and it may take 4 to 6 weeks before maximal benefits are evident)  Antidepressants must be taken for at least 6 to 9 months (even if feeling completely better, studies have shown that people who stop their medication during the first 6 months are much more likely to become depressed again)  Antidepressants are NOT addictive substances (antidepressants may elevate the moods of depressed individuals but do not acts as stimulants and are not associated with craving or other abuse patterns)

Remains one of the most commonly occurring

mental illnesses in adults, and it is often undiagnosed and untreated. Pharmacologic intervention is the cornerstone of antidepressant treatment. Antidepressant medications have a broad spectrum of neurochemical effects and influence a variety of receptors peripherally and centrally.

 American Psychiatric Association. Diagnostic and Statistical Manual of  

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Mental Disorders, 4th ed. American Psychiatric Association, 2000:356 Stahl SM. Blue genes and the mechanism of action of antidepressants. J Clin Psychiatry 2000;61:164-165 Delgado PL, Moreno FA, Potter R, et al. Norepinephrine and serotonin in antidepressant action: Evidence from neurotransmitter depletion studies. London, Marin Dunitz, 1997:141-163 Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders. Clin Pharmacol 1986;5:304-318 Katon W, Sullivan MD. Depression and chronic medical illness. J Clin Psychiatry 1990;51:3-11 American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry 2000;157:145 Rothschild AJ. Management of psychotic treatment-resistant depression. Psychiatr Clin North Am 1996;59:5-9 Ballenger JC. Clinical evaluation of venlafaxine. J Clin Psychopharmacol 1996;16:29-35 Gormon JM. Mirtazapine: Clinical overview. J Clin Psychiatry 1999;60:913