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Treatment Options for Depression

Each antidepressant medication has a response rate of approximately 60-80% and no antidepressant medication or class has been reliably shown to be more efficacious than another (1,2). It is widely accepted that it takes approximately 2 to 4 weeks of treatment before improvement is seen in emotional symptoms of depression, such as sadness and anhedonia (lack of pleasure or the capacity to experience it) (1,2). Furthermore, it may take as long as 6 to 8 weeks of treatment to see full benefit of antidepressant therapy (1,2).Since the typical major depressive episode lasts 6 months or longer, if antidepressant therapy is interrupted for any reason following the acute phase, the patient may relapse into the depressive episode (1,2). When treating the first depressive episode, antidepressants must be given for an additional 4 to 9 months in the continuation phase for the purpose of preventing relapse (1,2). Antidepressants have equivalent efficacy in groups of patients when given comparable doses (1,2). The initial choice for the antidepressant is made empirically, because one cannot predict which antidepressant will be the most effective in an individual patient (1,2). Factors that can affect the choice of the antidepressant used are the patient’s history of response, pharmacogenetics (history of the familial antidepressant response), the current medical history of the patient, presenting symptoms (fatique as compared to psychomotor agitation), possible drug drug interactions, adverse effects, patient preference and drug cost (1,2). If a patient fails to respond to one antidepressant class or one antidepressant drug within a class, it does not predict a failed response to another drug class or another drug within the class (1,2). 65 to 70% of patients with varying types of depression improve with drug therapy, which is compared with 30 to 40% who are well documented to improve with placebo. (1,2)

Mixed Serotonin and Norepinephrine Reuptake Inhibitors

The use of the TCAs has decreased greatly because of the emergence of equally effective therapies that are much safer in overdose and better tolerated (1,2). These are generally second line agents (1,2). TCAs can be lethal if overdosed. 70-80% die before reaching the hospital (1,2). This is despite TCAs being effective in treating all depressive subtypes (1,2). The TCAs have a narrow therapeutic index so that does that are less than 10 times the therapeutic daily dose may result in severe intoxication (1,2). Ingestion of 10-20 mg/kg could be potentially life threatening (1,2). Therefore this is not the first recommendation for KC.

The mechanism of active of all TCAs is the potentiating activity of NE and 5-HT by blocking their reuptake (1,2). But the potency and selectivity for inhibition of the reuptake of NE and 5-HT varies greatly among the agents (1,2). TCAs can affect other receptor symptoms that include cholinergic, neurologic, and cardiovascular systems (1,2,3).

Venlafaxine inhibits 5-HT reuptake at lower doses and has additional NE reuptake at higher doses (150 mg or higher) (1,2). This thus can be referred to as a serotonin-norepinephirne reuptake inhibitor (1,2). Duloxetine is also considered to be a SNRI, however, it has both 5-Ht and NE reuptake inhibition across all doses (1,2). TCAs are absorbed in the small intestine very rapidly and almost completely. It will enter the portal circulation and undergo first pass metabolism in the liver (1). The medication will enter the systemic circulation and bind to proteins which exceeds 90% (1). Only the free fraction is active (1). Metabolism and elimination is in the liver and the enzymes that metabolize the TCAs are 2D6, 1A2, 3A4, and 1C9 (1,2). The elimination half life is about 24 hours on average (1,2).

Side effects include sexual dysfunction, tremor, decreased seizure threshold and tremor. There is also an association with heart block, ventricular arrhythmias, and sudden death. Thus, patients must be screened for cardiac conduction system disease before the use of these medications. Anticholinergic side effects such as constipation, xerostomia, blurred vision and urinary retention may also be present (1). This medication may enhance the antiplatelet effect of Aspirin and may enhance the orthostatic hypotensive effect of MAO inhibitors (1). Onset may take 4-6 weeks (1).

Selective Serotonin Reuptake Inhibitors

SSRIs are generally considered to be first line antidepressants because they are safe in overdose and have improved tolerability (1,2). Furthermore, they have ease of dosing as another advantage (1,2). These agents are superior to placebo and comparable to other classes of antidepressants in treating patients with major depression (1,2). The time of onset (2-4 weeks) and the rate of response (60-70%) are comparable to TCAs (1,2). The mechanism of action is through the selective inhibition of the human serotonin transporter hSERT, which increases the serotonin concentrations at the nerve endings (1,2). It is used to treat depression by increasing the serotonergic activity. The serotonin reuptake pump is inhibited by 60-80% which increases the length of time that serotonin is available in the synapse and increases post synaptic receptor occupancy (1,2). There is little or no effect on the NE or dopamine reuptake. It does not appear that the full benefits for the treatment of depression is solely due to the reuptake inhibition as the reuptake inhibition occurs shortly after the initiation of the SSRI, however the full therapeutic effects of SSRIs may not appear for 3 to 8 weeks after (3,4). The full response may require downstream effects such as initial increase in synaptic serotonin, which will lead to increased production of neuroprotective proteins such as brain derived neurotrophic factors in the long term (3,4).

The advantage of this agent is that there is little or no effect on CVS compared to MAOIs or TCAs (3,4). The benefit of the side effect profile of SSRI is due to their selective nature (3,4). This is because none of the SSRIs affect the alpha-adrenergic, histaminic or cholinergic receptors except for paroxetine, which weak antagonizes the cholinergic receptor (3,4). The side effects of SSRIs are mainly due to the effects upon the seronotin receptors (3,4). The side effects of SSRIs affect the GI, CNS, and sexual function (3,4). There is an increase risk of GI bleeding and this is most pronounced in patients possess additional risk factors such as NSAID therapy, or a history of GI bleeding (3,4). Unlike GI and the CNS side effects of SSRI, the sexual dysfunction can persist during SSRI therapy and can involve impairment of arousal, desire and or orgasm (3,4). The non SSRI antidepressants such as bupropion, mirtazapine and moclobemide cause less sexual dysfunction and may be used instead (3,4). Particular CNS side effects include headache, sleep disturbance (insomnia, sommolence) dizziness, anorexia, tremor and nervousness (3,4). GI side effects include nausea, diarrhea, constipation, dry mouith and GI bleeding (3,4). This class of medications is the first choice for KC. Escitalopram is the stereoisomer of citalopram and has a similar side effect profile but is superior in terms of efficacy to citalopram and has a comparable efficacy to venlafaxine (3,4).

SSRIs are absorbed in the GI tract and reach peak plasma levels within 1 to 8 hours (3,4). The food does not affect the absorption and following absorption the SSRIs will bind to proteins and are widely distributed throughout the body (3,4). Metabolism and elimination of SSRIs are due to the liver (3,4). The half life is approximately 1 day for SSRIs. SSRIs are metabolized by CYP P450 2D6 isoenzyme (3,4). CYP P450 induces can decrease the effect of SSRIs and CYP P450 inhibitors can increase the effect and toxicity of SSRIs (3,4). This agents are cautioned in concomitant use of aspirin, NSAIDS or warfarin as the risk of bleeding may be potentiated (1). Caution is also advised with CNS depressants as the risk of sedation increases (1,2). MAO inhibitors should be avoided concomitant as there is a potential for serotonin syndrome which may result in coma, death, muscular rigidity and seizures (1,2).

Escitalopram. Initial dosing should be 10 mg in the morning (1,2). Older patients and patients that are sensitive to side effects can be started at a dose of 5 mg (1,2). The standard dose range is 10 to 20 mg once per day (1,2). The dose is titrated up in increments of 5 or 10 mg per day after one to four weeks (1,2).

MAO Inhibitors

MAOI are not first line medications for depression due to the dietary restrictions, drug-drug interactions and the extensive side effect profile (1,2). The blockage of MAOIa in the GI tract is responsible for a severe hypertensive crisis that can occur after patients ingest foods that contain tyramine (1,2). Tyramine is usually metabolized in the GI tract, but the inhibition of MAOIa will allow it to reach circulation (1,2). There are two isoforms of the MAO enzyme: MAO-A and MAO-B. MAO-A substrates include serotonin, while MAO-B substrates include phentylethylamine (1,2). Norepinephrine, epinephrine, dopamine, tyramine are substrates for both MAO-A and MAO-B (1,2). The inhibition of MAO will increase the concentrations of these amine compounds. Phenelzine and tranylcypromine inhibit both MAO enzymes nonselectively and it is an irreversible inhibition (1,2). It is suggested that the increase in the free serotonin and norepinephrine levels are responsible for the antidepressant effect of the drugs (1,2). MAOIs have potent hypotensive effects in which up to 50% of the patients will experience dizziness (1,2). This is an important considerable as when treating elderly patients they are more prone to the hypotensive effects and more likely to fall and sustain fractures (1,2). Dry mouth, GI effects, urinary hesitancy, headache and myoclonic jerks are common side effects. MAOis also suppress REM sleep and afternoon fatigue is common (1,2). This drug is useful for atypical depression (such as depression with hyperphagia, hypersomnia, leaden paralysis) and is frequently effective in treatment resistant depressed patients (1,2). MAO increases the concentrations of DA, NE and 5-HT that is present in the neuronal synapse by inhibiting the MAO enzyme (1,2). There are changes in receptor sensitivity (downregulation of beta adrenergic, alpha-adrenergic and serotonergic receptors) after chronic use (1,2). MAOI is well absorbed from the GI tract (1,2). The peak levels are reached in 2-3 hours and metabolism occurs in the liver through acetylation (1,2). It is excreted in the urine. MAOI may have a latent period of a few days to several months before any antidepressant activity may occur (1,2). The effects may persist for up to 3 weeks following the discontinuation of therapy (1,2). Concomitant use of MAOI and TCAs are contraindicated (1,2). Two weeks should elapse between discontinuation of the MAO or TCA therapy and the initiation with the other class of drugs (1,2). Serious and fatal reactions that include hyperpyrexia, confusion, myoclonus, diaphoresis, rigidity, seizures and cardiovascular disturbances have been reported when used concomitantly (1,2). These effects resemble serotonin syndrome but the underlying MOA may not be clear (3,4). MAOI may also potentiate the action of CNS depressants such as opiates or other analgesics, barbiturates, and sedatives (3,4). Caution should be advised when these agents are used concomitantly (3,4). Concomitant use of MAOI and DM is not recommended (3,4). This is because there have been case reports of psychosis (3,4). Furthermore, apparent serotonin syndrome has been reported upon concomitant administration (3,4). MAOIs are not a first choice for KC as it is for more refractory cases and require dietary control which may be difficult to adhere to.

Dual Action Agents

The actions of bupropion involve the reuptake inhibition of norepinephrine and dopamine (1,2). This is used as a first line agent for MDD (1,2). The contraindication is in patients that have seizure disorders or a history of anorexia (1,2). There is less GI disturbance and sexual dysfunction that occurs with bupropion compared to other SSRIs (1,2). The metabolism is through CYP2B6 in the liver (1,2). It is also an inhibitor of CYP2D6 (1,2). Excretion is mainly 87% as metabolites through the urine (1,2). MAOIs are contraindicated as it may increase the neurotoxic effects of bupropion (1,2). Adverse effects include tachycardia, headache, insomnia, dizziness, and xerostomia (1,2). This drug requires at least 2 weeks for a noticeable response in mood and up to 12 weeks for full therapeutic benefit (1,2).

Selective Workup of Venlafaxine

Indications

Venlafaxine is used for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder and off labelly for neuropathic pain. (1,2)

Mechanism of Action

Venlafaxine is a potent inhibitor of norepinephrine and serotonin reuptake and also weak inhibitors of dopamine reuptake. There is no activity on the muscarinic, alpha adrenergic or histamine receptors (1,2) Pharmacokinetics: Venlafaxine is absorbed orally and it undergoes minimal protein binding. Hepatic metabolism is extensive and the half life of the active metabolite is 11 hours (1). Contraindications include concurrent administration with MAOIs as it may result in serotonin syndrome (1). Patients that take venlafaxine may experience increases in both systolic and diastolic blood pressure (1). Preexisting hypertension should be controlled prior toward starting venlafaxine (1). Caution is recommended when using venlafaxine with NSAIDS, aspirin or other drugs that affect coagulation (1). There is also a risk of hypoatremia (1). This risk is higher in patients that are elderly (1). Onset requires 2 weeks for noticeable response in mood and the pull benefits should be seen in 12 weeks (1). Adverse effects include nausea headache, insomnia, dizziness, dry mouth and sexual dysfunction (1). Venlafaxine is not a potent inhibitor of the CYP450 enzymes (1). The use of this is contraindicated within 14 days of a MAOI use (1)

References

  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 7th ed. Toronto: McGraw-Hill; 2007. p. 1123
  2. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 569.
  3. American Psychiatric Association. Practice guideline for the treatment of major depressive disorder, third edition. Am J Psychiatry 2010; 167:10 (supplement).
  4. Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research Practice Guidelines. Arch Gen Psychiatry. 1998; 55:1121.

Disclaimer

This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers


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