Depression: Overview and Treatment Options

Authors: Scott Kiker, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University;

Kayla Osbourn, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University;

Sean Murphy, Pharm.D. Candidate, Harrison School of Pharmacy, Auburn University;

Wesley T. Lindsey, Pharm.D., Associate Clinical Professor in Drug Information, Drug Information and Learning Resource Center Harrison School of Pharmacy, Auburn University

Universal Activity #: 0178-0000-15-101-H01-P | 1.25 contact hours (.125 CEUs)

Initial Release Date: March 1, 2015 | Expires: March. 1, 2017

Alabama Pharmacy Association | 334.271.4222 | www.aparx.org | [email protected]

SPRING 2015: CONTINUING EDUCATION | WWW.APARX.ORG 1 Authors have no relevant financial relationships to disclose.

EDUCATIONAL OBJECTIVES After the completion of this activity pharmacists will be able to: • Describe two popular hypotheses used to explain the physiologic cause of depression. • List criteria used to diagnose depression or MDD. • Discuss pharmacologic treatment options for depression.

INTRODUCTION Depression is a chronic illness that is common among all neurotransmitters which causes an almost immediate response ethnicities.1 The typical onset of depression occurs in the late 20s in the neurotransmitter levels; however, full clinical effect does and the estimated lifetime prevalence is 5-12% in men and 9-26% not occur for several weeks. In addition, not all patients with in women. Depression appears to be more common in lower depression have decreased levels of NE, DA, and 5-HT, and some socioeconomic classes and genetic factors may also contribute. may even have higher levels than normal. The mechanism of Patients are 2.7 times more likely to develop depression if one efficacy in depression is thought to be through alterations in the parent has been diagnosed and 3 times more likely if both parents balance of DA, 5-HT, and NE receptors, most importantly the have been diagnosed with depression. Other factors that increase down-regulation of 5-HT1A presynaptic receptors that provide the likelihood of becoming depressed include a difficult childhood, negative feedback. abuse, chronic illnesses such as rheumatoid arthritis and AIDS, A second hypothesis is the dysregulation hypothesis.1,2 self-esteem issues, the death of a loved one, the ending of a Instead of having decreases in the levels of neurotransmitters, serious relationship, and unemployment. Although most people this hypothesis simply states that the neurotransmitter system is experience depressive symptoms at some time during their lives, out of balance. The dysregulation can be due to problems such depressive disorders involve clinically-relevant symptoms that can as impaired homeostasis or regulatory mechanisms, changes in have devastating consequences if left untreated.1,2 The American basal rate of release of neurotransmitters, or disruption in normal Psychiatric Association recently published the fifth edition of the rhythms such as the circadian rhythm. Diagnostic and Statistical Manual of Mental Disorders (DSM-V).3 This manual provides the diagnostic criteria for major depressive SYMPTOMS OF DEPRESSION disorder (MDD) which is based mainly on subjective symptoms. There are classes of depression symptoms that can be used to Clinical depression is a medical condition classified in help guide in diagnosis.2 Emotional symptoms of depression include DSM-V as either 1) a single episode of major depressive disorder, a diminished ability to experience pleasure and loss of interest in 2) recurrent major depressive disorder or 3) depressive disorder activities, hobbies, or work. A depressed patient will appear sad not otherwise specified.1,2,3 People usually experience recurrent and often have a pessimistic attitude. Feelings of worthlessness or symptoms of major depression. The overall prevalence of MDD guilt may prompt thoughts of suicide. The guilt may be unrealistic, in the United States is 7%. Females are 1.5 to 3 times more likely inappropriate, or misplaced and can extend to delusional thoughts to experience depression compared to males. The risk of recurrent as well. Anxiety is present in almost 90% of depressed patients. depressive episodes increases with each episode (50% risk after The emotional symptoms can progress to psychotic features such as the first episode, 70% after the second, etc.). Furthermore, risk auditory hallucinations encouraging suicide. factors for recurrent episodes include severe preceding episodes and Physical symptoms of depression are chronic fatigue, appetite young age at onset of initial episode. The risk of recurrent episodes disturbances, sleep disturbances, and sexual dysfunction.2 The decreases as the duration of remission increases. Significant fatigue is often worse in the morning and does not improve with functional disability, morbidity and mortality are all associated with rest. Accompanying it can be pain and headaches. The fatigue depression. Treatment with improves the symptoms can impair the ability to perform normal daily tasks. Appetite of depression, increases the level of functioning and helps to disturbances can result in substantial weight loss from decreased prevent further episodes of depression. Response to treatment appetite or weight gain from food cravings. varies with 20% of patients experiencing improvement within 3 Intellectual or cognitive symptoms include impaired months and 80% experiencing improvement within 1 year. concentration, slowed thinking, poor short term memory of recent events, confusion, or indecision.2 When elderly patients PATHOPHYSIOLOGY display cognitive symptoms, depression should be considered. Two popular hypotheses have been generated to explain the Psychomotor disturbance symptoms can manifest as slowed speech physiologic cause of depression.1,2 The oldest is the monoamine or movements or even as psychomotor agitation resulting in restless hypothesis which links depression to decreases in levels of the motion such as fidgeting or pacing. neurotransmitters (NE), (DA), and (5-HT) in the brain. This hypothesis does not adequately DIAGNOSTIC CRITERIA explain depression for several reasons. The most common The standard for diagnosing depression or MDD has been medications used for depression block the reuptake of these set by the Diagnostic and Statistical Manual of Mental Disorders,

2 ALABAMA PHARMACY ASSOCIATION | SPRING 2015: CONTINUING EDUCATION 5thed (DSM-V).3 The important feature of a major depressive o Note: This exclusion does not apply if all of the episode is presence of symptoms throughout most of the day, manic-like or hypomanic-like episodes are substance- nearly every day, for two consecutive weeks. The practitioner must induced or are attributable to the physiological effects be able to probe beneath surface level questions and responses (to of another medical condition.” minimize under-diagnosis), and differentiate between grief and depression (to minimize over-diagnosis). The following are the GRIEF VERSUS MDD criteria taken directly from the DSM-V. The DSM-V has made a point to distinguish between A. “Five (or more) of the following symptoms have been MDD and depressive symptoms caused by grief or response present during the same 2-week period and represent a to a significant loss.3 There are distinguishable characteristics change from previous functioning; at least one of the that separate a diagnosable condition from a transient state of symptoms is either (1) depressed mood or (2) loss of mind. Grief symptoms may include sadness, insomnia, change interest or pleasure. in appetite or weight loss, which resemble Criterion A of the o Note: Do not include symptoms that are clearly diagnostic criteria listed above. Attributing these symptoms to attributable to another medical condition. either MDD or grief requires careful consideration and extensive 1. Depressed mood most of the day, nearly every day, as clinical judgment. The predominant symptoms of grief are feelings indicated by either subjective report (e.g., feels sad, of emptiness and loss contrasted to the inability to experience empty, hopeless) or observation made by others (e.g., happiness or pleasure in MDD. During the grieving process, appears tearful). (Note: In children and adolescents, these feelings tend to decrease in intensity over a period of time can be irritable mood.) depending on the cause and occur in waves while the mood 2. Markedly diminished interest or pleasure in all, or changes in MDD are persistent and are not tied to any specific almost all, activities most of the day, nearly every thought or idea. Grief can be accompanied with thoughts and day (as indicated by either subjective account or memories of the deceased rather than pessimistic or self-loathing observation). thoughts seen in MDD. 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight PHARMACOLOGIC TREATMENT in a month), or decrease or increase in appetite nearly Classes of antidepressants include monoamine oxidase every day. (Note: In children, consider failure to inhibitors (MAOs), antidepressants (TCAs), selective make expected weight gain.) serotonin reuptake inhibitors (SSRIs), selective norepinephrine 4. Insomnia or hypersomnia nearly every day. reuptake inhibitors (SNRIs), serotonin antagonists and 5. Psychomotor agitation or retardation nearly every day reuptake inhibitors (SARIs) and other neurotransmitter-altering (observable by others, not merely subjective feelings medications. Medications recently approved for depression include of restlessness or being slowed down). (Viibryd) in 2011 as well as (Fetzima) 6. Fatigue or loss of energy nearly every day. and (Brintellix) in 2013.4,5 Almost all antidepressants 7. Feelings of worthlessness or excessive or inappropriate carry the following Black Box Warning (BBW): Antidepressants guilt (which may be delusional) nearly every day (not increased the risk compared to placebo of suicidal thinking and merely self-reproach or guilt about being sick). behavior (suicidality) in children, adolescents, and young adults in 8. Diminished ability to think or concentrate, or short-term studies of major depressive disorder (MDD) and other indecisiveness, nearly every day (either by subjective psychiatric disorders.2 The recommended stepwise pharmacologic account or as observed by others). approach to treating depression is outlined in Table 1.2 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or SELECTIVE SEROTONIN REUPTAKE INHIBITORS a suicide attempt or a specific plan for committing (SSRIS) suicide. SSRIs work by inhibiting the reuptake of serotonin into the presynaptic neuron.6,7,8 This causes an increase in the level of The symptoms cause clinically significant distress or serotonin available in the synaptic cleft allowing for increased impairment in social, occupational, or other important binding of postsynaptic serotonin receptors. SSRIs are frequently areas of functioning. used to treat depression with approximately 65-75% of patients The episode is not attributable to the physiological effects seeing improvement in their symptoms after initiation of an of a substance or to another medical condition. SSRI. These agents are considered first line therapy due to their The occurrence of the major depressive episode is not increased safety and tolerability compared to other classes of 2 better explained by schizoaffective disorder, , antidepressants. SSRIs have very little affinity for muscarinic, schizophreniform disorder, delusional disorder, or other GABA, benzodiazepine, alpha, beta, , and histamine specified and unspecified schizophrenia spectrum and receptors; therefore, they demonstrate less cardiovascular, other psychotic disorders. anticholinergic, and sedative side effects seen with other antidepressants. Dosing recommendations for the SSRIs are There has never been a manic episode or a hypomanic episode. outlined in Table 2.6,7,8

SPRING 2015: CONTINUING EDUCATION | WWW.APARX.ORG 3 Table 1. Treatment Comments Step 1 SSRIs Assumption that there are no contraindications

Step 2 Continue treatment with SSRI used in step Appropriate for all patients who experience an adequate 1 for at least 4 to 9 months response or complete remission Changing to a different Appropriate for patients who have no or partial response to SSRI or to a Non-SSRI treatment in step 1 or significant adverse effects Adjunctive therapy or augmentation Appropriate for patients who experience a partial response after optimizing the dose of the treatment started in step 1

Step 3 Continue treatment started in step 2 for at Appropriate for all patients who experience an adequate least 4 to 9 months response or complete remission

Switch to a non-SSRI antidepressant Appropriate for all patients who have failed to achieve an adequate response from treatment started in step 2

Consider adjunctive treatment with a non- Appropriate for patients who experience a partial response after SSRI or augmentation optimizing the dose of the treatment started in step 2

Table 2. SSRI: Initial Dose: Max Dose: Special Populations: 20 mg daily 40 mg/day Geriatric (>60 years): 20 mg daily (initial and max) (Celexa) Children (>9 years): 10-40 mg Hepatic impairment: 20 mg daily is max dose Renal impairment: no adjustment

Escitalopram 10 mg daily 20 mg/day Geriatric: 10 mg daily (Lexapro) Children (>12 years): 10 mg daily Hepatic impairment: 10 mg daily is max dose Renal impairment: no adjustment 20 mg daily or 80 mg/day Children (>8 years): 10-20 mg daily (Prozac) 90 mg once weekly Hepatic impairment: no adjustment Renal impairment: no adjustment

Fluvoxamine 50 mg QHS 300 mg/day Children (Luvox) 100 mg (CR) QHS 8-11 years: Initially 25 mg QHS, max dose is 200 mg/day 12-17 years: Initially 25 mg QHS, max dose is 300 mg/day Hepatic impairment: no adjustment Renal impairment: no adjustment 20 mg daily 50 mg/day Geriatric: 10 mg daily, max dose is 40 mg/day (Paxil) 25 mg (ER) daily Children: safety has not been established Hepatic impairment: max dose is 40 mg/day Renal impairment: No adjustment

Sertraline 25 mg daily 200 mg/day Children: same as adult (Zoloft) Hepatic impairment: no adjustment Renal impairment: no adjustment

4 ALABAMA PHARMACY ASSOCIATION | SPRING 2015: CONTINUING EDUCATION Table 3.

Anticholinergic Orthostatic Conduction Sedation Seizures Effects Hypotension Abnormalities SSRI: Citalopram None Very little None Little None

Escitalopram None None None None None Fluoxetine None None None Low None None None None Low None Paroxetine Very little Very little None Low None None None None Low None Adapted from Dipro’s Chapter 77: Major Depressive Disorder

All of the SSRIs undergo hepatic cytochrome (CYP) are highly plasma protein bound so caution should be used when metabolism.6,7,8 Citalopram, escitalopram, and fluvoxamine are they are administered with other highly plasma protein bound specifically metabolized by CYP 3A4 so drug-drug interactions are drugs such as warfarin or digoxin. Drugs that interfere with the highly likely with these three agents. Patients starting fluoxetine reuptake of serotonin when combined with drugs interfering with should wait at least 2 weeks after discontinuing an MAOI before blood clotting (NSAIDs, aspirin, warfarin) can increase the risk of initiating fluoxetine. If initiating an MAOI in a patient previously gastrointestinal bleeds. The risk of occurrence of some specific side taking fluoxetine, wait at least 5 weeks following discontinuation effects of the SSRIs are ranked in Table 3.2 Paroxetine causes the of fluoxetine before starting the MAOI. All of the SSRIs are Food most weight gain compared to all other SSRIs. The SSRIs that are and Drug Administration (FDA) pregnancy risk category C, least likely to cause sexual dysfunction are citalopram, fluoxetine, except paroxetine which is category D. Abrupt discontinuation and fluvoxamine. Patients being treated with an SSRI should see of an SSRI may result in symptoms including: agitation, anxiety, relief of symptoms within 4-6 weeks and should be re-evaluated at confusion, dizziness, headache, insomnia, or irritability. SSRIs this time for efficacy.

Table 4.

Initial Dose: Max Dose: Special Populations: SNRI: 40-60 mg/day 60 mg/day Geriatric: May initiate at lower dose (Cymbalta) Hepatic Impairment: Contraindicated Renal Impairment: Do not use in CrCl < 30 mL/min or end stage renal disease Venlafaxine IR: 75 mg/day IR: 225-375 mg/day Geriatric: May initiate at lower dose (Effexor) ER: 37.5-75 mg/day ER: 225 mg/day Hepatic Impairment: Reduce total daily dose by 50% Renal Impairment: GFR: 10-70 mL/min: Reduce total daily dose by 25% to 50% Hemodialysis: Reduce total daily dose by 50%

Desvenlafaxine 50 mg/day 50 mg/day Geriatric: Same as adult dosing (Pristiq) Hepatic Impairment: Moderate to severe impairment: 50 mg/day Renal Impairment: CrCl 30-50 mL/min: Max of 50 mg/day CrCl <30 mL/min: Max of 50 mg every other day Hemodialysis: Max of 50 mg every other day 50 mg BID 200 mg/day Geriatric: Same as adult dosing (Savella) Hepatic Impairment: No adjustment Renal Impairment: CrCl ≤29 mL/min: 25 mg BID Do not use in end stage renal disease

SPRING 2015: CONTINUING EDUCATION | WWW.APARX.ORG 5 SEROTONIN/NOREPINEPHRINE REUPTAKE NOREPINEPHRINE/DOPAMINE REUPTAKE INHIBITOR INHIBITORS (SNRIS) () The SNRIs include duloxetine (Cymbalta), Bupropion (Wellbutrin) works by inhibiting the neuronal (Effexor), (Pristiq), and milnacipran (Savella).18,19,20 reuptake of norepinephrine and dopamine.23,24 There are various The SNRIs work by inhibiting the reuptake of both serotonin dosage forms of bupropion available including immediate release and norepinephrine into the presynaptic neuron. Dosing (IR), sustained release (SR), and extended release (ER). The dosing recommendations for the SNRIs are outlined in Table 4.18,19,20 recommendations for the various dosage forms are outlined in All SNRIs are hepatically metabolized.18,19,20 These agents Table 6.23,24 are contraindicated in patients with uncontrolled closed angle In geriatric patients, dosing should start at 37.5 mg IR BID glaucoma. The SNRIs are FDA pregnancy category C. Possible up to 300 mg/day.23,24 In pediatric patients, bupropion should side effects of the SNRIs include hypertension, tachycardia, be dosed at 1.4-6 mg/kg/day. A reduction in dose or frequency sweating, increased risk of bleeding, and insomnia. Antidepressant should be considered in patients with renal or hepatic impairment. results should be seen by 2-3 weeks after starting an SNRI. The The maximum dose is reduced to 75 mg IR daily in patients with use of an SNRI is as an alternative in patients with MDD who severe hepatic impairment. Common side effects of bupropion are have responded poorly to SSRIs.2 tachycardia, headache, insomnia, dizziness, xerostomia, weight loss, nausea, and anxiety. Contraindications include seizure disorder, SEROTONIN ANTAGONISTS AND REUPTAKE history of anorexia or bulimia, and use in patients undergoing INHIBITORS (SARIS) abrupt discontinuation of ethanol or sedatives. Bupropion is The SARIs include (Oleptro) and hepatically metabolized by CYP2B6 and is FDA pregnancy (Serzone).21,22 The SARIs have been shown to inhibit the reuptake category C. Bupropion may be chosen over other antidepressants of serotonin and antagonize 5HT2A/ serotonin receptors. because of its reduced risk of anticholinergic side effects, The dosing recommendations for trazodone and nefazodone are cardiovascular side effects, antihistaminic side effects, weight gain, outlined in Table 5.21,22 and sexual dysfunction.2 Bupropion may have benefit in patients Trazodone and nefazodone both undergo hepatic metabolism with refractory depression, and it is commonly used as adjunct to active metabolites.21,22 Nefazodone has a BBW for hepatic rather than as monotherapy. failure. Common side effects of the SARIs include constipation, nausea, dizziness, and headache. The SARIs are FDA pregnancy (REMERON) category C. It may take 2-4 weeks for the SARIs’ antidepressant Mirtazapine acts as a central α-2 effect to be seen. These drugs are considered 3rd line agents if the antagonist that increases the release of norepinephrine and use of SSRIs, SNRIs, and TCAs has failed.2 Trazodone can also be serotonin.13,14 It is also a potent 5-HT2 and 5-HT3 receptor used as adjunctive treatment to help patients fall asleep. antagonist which decreases the incidence of adverse effects like insomnia and nausea seen with SSRIs. It is also a significant H1 antagonist which is why it can cause some sedation. It is

Table 5.

Initial Dose: Max Dose: Special Populations: SARI: Trazodone 150 mg/day in three 600 mg/day; ER: Geriatric: (Oleptro) divided doses 375 mg/day IR: 25-50 mg QHS with 25-50 mg/day increase weekly ER: 150 mg QHS ER: Same as adult dosing Children: 6-12 years old: Initial: 1.5-2 mg/kg/day in divided doses; max: 6 mg/kg/day in 3 divided doses Adolescents: Initial: 25-50 mg/day; increase to 100-150 mg/ day in divided doses Hepatic Impairment: No adjustment Renal Impairment: No adjustment

Nefazodone 200 mg/day in two 600 mg/day in two Geriatric: Initial: 50 mg BID; usual maintenance dose: 200-400 (Serzone) divided doses divided doses mg/day Hepatic Impairment: No adjustment Renal Impairment: No adjustment IR: immediate release; ER: extended release

6 ALABAMA PHARMACY ASSOCIATION | SPRING 2015: CONTINUING EDUCATION Table 6.

Initial Dose: Max Dose: Bupropion Immediate Release Hydrochloride Salt 100 mg BID 150 mg TID Sustained Release Hydrochloride Salt 150 mg daily 200 mg BID Extended Release Hydrochloride Salt 150 mg daily 450 mg daily Extended Release Hydrobromide Salt 174 mg daily 522 mg daily also a moderate α-1 antagonist which is why it may cause some All MAOIs except phenelzine undergo hepatic orthostatic hypotension. Mirtazapine is considered a second line metabolism.9,10,11,12 Contraindications to MAOIs include treatment for MDD behind the SSRIs.2 When initiating treatment pheochromocytoma, abnormal liver function tests or history with mirtazapine, it should be started at 15 mg QHS and titrated of hepatic disease, and renal disease or impairment. In general, up every 2 weeks if needed to a maximum dose of 45 mg QHS. one should wait at least 2 weeks after discontinuing an MAOI Mirtazapine is hepatically metabolized by CYPs 2D6, 1A2, and before initiating therapy with another antidepressant. One should 3A4. Mirtazapine has not been proven safe for use in children. also wait 2 weeks after discontinuing therapy with another Common side effects of mirtazapine include increased appetite, antidepressant before initiating MAOI therapy. MAOIs should weight gain, increased triglycerides, constipation, dry mouth, and never be administered in combination with another antidepressant. somnolence. Mirtazapine is FDA pregnancy category C. It will Side effects of MAOIs include orthostatic hypotension, anxiety, take 1-2 weeks to begin seeing the effects of mirtazapine and 2-4 dizziness, fatigue, insomnia, seizure, tremor, weight gain, weeks to see its full effect. constipation, sexual dysfunction, blurred vision, and jaundice. All MAOIs are FDA pregnancy category C. Patient counseling is TRICYCLIC ANTIDEPRESSANTS (TCAS) of utmost importance with the MAOIs.2 Information provided The TCAs include (Elavil), should include that 2-3 weeks may be needed to see a decrease in (Tofranil), (Pamelor), (Norpramin), symptoms. Patients should avoid , caffeine, and tyramine- (Silenor), and (Anafranil).15,16,17 The TCAs containing foods (cheese, yogurt, beer, sardines, processed meats, work by decreasing the reuptake of norepinephrine and serotonin liver, chocolate, soy sauce, sauerkraut, and licorice). within the CNS. Dosing recommendations for the TCAs are listed in Table 7.15,16,17 HYPERICUM PERFORATUM (ST. JOHN’S WORT) The TCAs are metabolized in the liver.15,16,17 Contraindications Meta-analyses of quality clinical trials support the role of to the TCAs include recent heart attack and narrow angle St. John’s Wort in the treatment of depression.25,26 Effectiveness is glaucoma. The list of side effects of the TCAs is extensive. comparable with standard antidepressants, while adverse events Common side effects include orthostatic hypotension, weight are lower than with conventional antidepressants; however, gain, sedation, and anticholinergic effects (urinary retention, interactions with other drugs and quality control issues may blurred vision, memory impairment). Nortriptyline causes the least limit its use. Research has shown that St. John’s Wort extracts anticholinergic effects and sedation and is the preferred choice are more effective than placebo, likely as effective as low dose when choosing a TCA.2 It will take 2 weeks or more to see the TCAs, and likely as effective as the SSRIs fluoxetine, sertraline, full anti-depressant effect of these drugs. The TCAs are effective at and paroxetine.27 Short-term response rates to St. John’s Wort treating depression, but they are not the drugs of choice due to the appear to be between 65% and 100%; however, long-term, the large number of side effects associated with them. response rates appear to be lower, 60% to 69%. Hyperforin is one of the main components of St. John’s Wort.25,26 It is thought to MONOAMINE OXIDASE INHIBITORS (MAOIS) be responsible for the antidepressant effects by causing inhibition MAOIs work by binding to and inhibiting the activity of the of the reuptake of serotonin, dopamine, and norepinephrine. monoamine oxidase (MAO) enzyme.9,10,11,12 Reduction of MAO Hyperforin is a CYP3A4 inducer which leads to numerous drug activity causes an increased concentration of neurotransmitters, interactions. St. John’s Wort capsules or tablets should be dosed such as epinephrine, norepinephrine, and dopamine, at various at 300 mg TID with a maximum dose of 1200 mg/day. Liquid storage sites in the CNS and sympathetic nervous system. While extracts should be dosed at 2-4 mL TID, and St. John’s Wort tea MAOIs have been proven effective in treating depression, they are should be consumed as a single dose of 2-3 g. Contraindications to no longer considered first line agents due to the numerous side St. John’s Wort include pregnancy, HIV/AIDs, MAOI therapy, and effects and interactions associated with this class of drugs.2 The severe depression with suicidal ideation. There is a lack of clinical MAOIs have been replaced by other drugs (SSRIs) that are safer data for the safety and efficacy of St. John’s Wort in children. and effective at relieving the symptoms of depression. Dosing Common side effects of St. John’s Wort include nausea, vomiting, recommendations for the MAOIs are listed in Table 8.9,10,11,12 constipation, diarrhea, itching, fatigue, headache, dizziness, and

SPRING 2015: CONTINUING EDUCATION | WWW.APARX.ORG 7 Table 7.

Initial Dose: Max Dose: Special Populations: TCA: Amitriptyline 50-150 mg/day in 300 mg/day Geriatric: 10-25 mg QHS (Elavil) a single dose at Children: bedtime or in Do not use if < 12 years old divided doses 9-12 years: 1 mg/kg/day in 3 divided doses Max dose: 3 mg/kg/day Adolescent: Initial 25-50 mg/day Max dose: 100 mg/day Hepatic Impairment: No adjustment Renal Impairment: No adjustment

Imipramine 75 mg/day 200 mg/day Geriatric: Initial: 25-50 mg QHS (Tofranil) Max Dose: 100 mg/day Children: Initial: 1.5 mg/kg/day Increase by 1 mg/kg/day every 3-4 days Max Dose: 5 mg/kg/day Hepatic Impairment: No adjustment Renal Impairment: No adjustment Nortriptyline 25 mg 3-4 times a 150 mg/day Geriatric: Initial: 30-50 mg QHS (Pamelor) day Children: 1.5 mg/kg/day Increase in 1-3 mg/kg/day increments Hepatic Impairment: Use lower doses and slower titration Renal Impairment: No adjustment Desipramine 100-200 mg/day 300 mg/day Geriatric: (Norpramin) Initial: Start at lower dose Maintenance dose: 25-100 mg/day Max Dose: 150 mg/day Children: Do not use if < 6 years old 6-12 years: 1-3 mg/kg/day Max Dose: 5 mg/kg/day Adolescents: Initial dose: Start at lower dose Maintenance Dose: 25-100 mg/day Max Dose: 150 mg/day Hepatic Impairment: No adjustment Renal Impairment: No adjustment Doxepin 25-150 mg QHS or 300 mg/day Geriatric: (Silenor) in 2-3 divided doses Initial: 10-25 mg QHS Increase by 10-25 mg weekly Max Dose: 75 mg/day Children: Children < 12 years: 1-3 mg/kg/day Children >/= 12 years and Adolescents: Initial: 25-50 mg /day Max Dose: 100 mg/day Hepatic Impairment: Use lower doses and slower titration Initiate Silenor at 3 mg once daily Renal Impairment: No adjustment

8 ALABAMA PHARMACY ASSOCIATION | SPRING 2015: CONTINUING EDUCATION Clomipramine 25 mg/day 250 mg/day Geriatric: Same as adult dosing (Anafranil) Children: Initial Dose: 25 mg/day Max Dose: 3 mg/kg/day or 200 mg/day, whichever is smaller Hepatic Impairment: No adjustment Renal Impairment: No adjustment

Table 8.

Initial Dose: Max Dose: Special Populations: MAOI: Phenelzine 15 mg TID 90 mg/day Geriatric: begin with 15 mg QAM with gradual titration to (Nardil) 60 mg/day Children: contraindicated Hepatic Impairment: contraindicated Renal Impairment: contraindicated Selegiline Transdermal Patch: 12 mg/day Geriatrics (>/= 65 years): 6 mg/24 hour patch (Emsam) 6 mg/24 hours Children < 12 years: do not use applied once daily Hepatic Impairment: no dosage adjustment Renal Impairment: no dosage adjustment

Tranylcypromine 30 mg/day in 60 mg/day Geriatric: low initial doses with gradual increases (Parnate) divided doses Children < 16 years: do not use Hepatic Impairment: contraindicated Renal Impairment: contraindicated

Isocarboxazid 10 mg 2-4 times/day 60 mg/day Geriatric: low initial doses with gradual increases (Marplan) Hepatic Impairment: contraindicated Renal Impairment: contraindicated photosensitivity. It is important to remember that St. John’s Vilazodone is FDA pregnancy category C. Side effects are similar Wort is not FDA approved, and it interacts with many other to those of the other SSRIs with sexual dysfunction being reported medications; however, St. John’s Wort is a natural alternative for less with vilazodone. Patients should begin to see an antidepressant patients with MDD who want a cheaper option and want to avoid effect within 2-3 weeks of starting vilazodone. Vilazodone appears prescription medications.2 to have similar efficacy and tolerability to the other SSRIs. Two randomized, double-blind, placebo-controlled trials showed that DRUGS RECENTLY APPROVED vilazodone is effective in adult patients with MDD with tolerable Vilazodone (Viibryd) is an SSRI and a partial agonist of side effects.29,30 Tests used to compare vilazodone to placebo 5HT1A receptors that was approved in January 2011.28 The included Montgomery-Asberg Depression Rating Scale (MADRS), recommended dosing technique is 10 mg daily for 7 days, then the 17-item Hamilton Depression Rating Scale (HDRS-17), the 20 mg daily for 7 days, then 40 mg daily. Titration of the dose 21-item Hamilton Depression Rating Scale, Hamilton Anxiety in this manner helps decrease the occurrence of GI-related Rating Scale (HARS), Clinical Global Impressions-Severity of adverse effects when vilazodone is first initiated as well as aid Illness (CGI-S), and Clinical Global Impressions-Improvement the physician in deciding upon the lowest effective dose for the (CGI-I). Vilazodone treatment groups consistently had improved patient. The maximum dose is 40 mg/day or 20 mg/day if the symptoms from baseline based on each test compared to placebo. patient is also taking a strong CYP3A4 inhibitor or has intolerable Vilazodone did not achieve higher remission rates compared to side effects with a moderate CYP3A4 inhibitor. CYP3A4 is a placebo; however, this was most likely due to the short duration of 8 major metabolizer of vilazodone. This drug has not been studied weeks in each study. Although clinical data is lacking, monotherapy in children, and there is no dosage adjustments needed for renal with vilazodone may be a viable option to combination therapy of impairment, hepatic impairment, or in the elderly. Vilazodone has and SSRIs for the treatment of MDD. A randomized a BBW regarding its ability to increase the risk of suicide in young clinical trial is currently under development comparing vilazodone adults. Contraindications include concomitant use of an MAOI, to citalopram.31 The usefulness of vilazodone may be further defined use of vilazodone within 14 days of discontinuing an MAOI, and when clinical data from this trial becomes available. use of an MAOI within 14 days of discontinuing vilazodone.

SPRING 2015: CONTINUING EDUCATION | WWW.APARX.ORG 9 Levomilnacipran (Fetzima) is a potent and selective inhibitor a buprenorphine/samidorphan combination, , of norepinephrine and serotonin reuptake (SNRI) approved in July liafensine, and GLYX 13.39 Pipamperone, a of 2013.32 Levomilnacipran predominately enhances the effect of 4 (D4) and 5HT2A , has been shown to norepinephrine. As with vilazodone, a specific dosing technique enhance the antidepressant effect of citalopram. Buprenorphine, is recommended when levomilnacipran is initiated in order to a partial agonist of the mu receptor in combination with decrease the occurrence of adverse effects, specifically orthostatic samidorphan, an antagonist of mu opioid receptors is thought to hypotension, and determine the lowest effective dose. The patient be a potential non-addictive treatment for depression. Amitifadine should start with 20 mg/day for 2 days then increase to 40 mg/ and liafensine are both nonselective reuptake inhibitors of day on day 3. This dose may then be increased in increments serotonin, dopamine and norepinephrine. Amitifadine failed of 40 mg at intervals of 2 or more days. Maintenance dosing to achieve a significant difference compared to placebo in the is 40-120 mg/day, and the maximum dose is 120 mg/day. No improvement of the MADRS score; however, the investigators dosage adjustments are required for elderly patients or patients believe that this was due to subtherapeutic dosing. GLYX 13 is a with hepatic impairment. Levomilnacipran is not approved for partial agonist of the N-Methyl-D-aspartate (NMDA) receptor. use in children, and the dose must be adjusted based on creatinine Results from phase II trials have suggested that GLYX 13 may clearance in patients with renal impairment. Contraindications be useful in treatment-resistant depression and may also offer to levomilnacipran include hypersensitivity to milnacipram, a more rapid response to treatment compared to traditional uncontrolled narrow-angle glaucoma, and use of an MAOI antidepressants. concurrently, within 7 days of discontinuing levomilnacipran, or Clinical trials have demonstrated the efficacy of in within 2 weeks of discontinuing an MAOI. Levomilnacipran has a treatment-resistant depression.40,41 Currently, an ongoing study BBW for its ability to increase risk of suicide in young adults. This suggests that the antidepressant effect seen with ketamine is due drug is FDA pregnancy category C, and its most common side to the increased glutamate and gamma aminobutyric acid (GABA) effects are orthostatic hypotension and nausea. Levomilnacipran levels seen in the brain after ketamine administration.42 The is extensively metabolized by CYP3A4 in the liver. Two purpose of this trial is to determine how ketamine works in the randomized, placebo controlled trials showed that sustained release treatment of depression. Evidence provided in this trial may aid in levomilnacipran significantly improved depressive symptoms the development of future glutamate and GABA-enhancing drugs compared to placebo.33,34 Both trials showed that levomilnacipran that are orally available. was generally well tolerated. The levomilnacipran group did not achieve a higher remission rate compared to placebo; however, CONCLUSION the study was limited due to its short duration. Due to the potent Depression is most commonly a chronic condition requiring inhibition of norepinephrine reuptake, levomilnacipran may be pharmacologic treatment. Antidepressants have various effects on useful in treating the depressive symptoms associated with the the nervous system both centrally and peripherally. Response to noradrenergic symptom cluster in depression. These symptoms therapy usually takes several weeks. Changes in therapy should include functional impairment, concentration problems, lassitude, be considered if patients fail to achieve adequate response to their psychomotor retardation, and reduced self-care. initial treatment. Older medications, such as MAOIs and TCAs, Vortioxetine (Brintellix) is a serotonin reuptake inhibitor, should be reserved for patients who fail therapy with second 5-HT1A agonist, and 5-HT3 antagonist approved in September generation antidepressants. Medications are currently under of 2013.35,36 It is dosed initially at 10 mg/day and can be increased development that may be useful in treatment-resistant depression to 20 mg/day as tolerated. A dose of 5 mg/day may be considered and may also offer a more rapid response to therapy. for patients who do not tolerate higher doses. The maintenance dose of vortioxetine is usually 5-20 mg/day. This drug is not approved for use in children, and there are no dosage adjustments required for elderly patients or patients with renal impairment. Vortioxetine is not recommended for use in patients with severe hepatic impairment. Contraindications to vortioxetine include use of an MAOI concurrently or within 21 days of discontinuing vortioxetine or within 14 days of discontinuing the MAOI. Vortioxetine has a BBW for its ability to increase risk of suicide in young adults. This drug is FDA pregnancy category C, and its most common side effects are nausea and sexual dysfunction. Vortioxetine is extensively metabolized by CYP3A4. Two clinical trials demonstrated that vortioxetine is well tolerated; however, both of these studies failed to demonstrate improvement of symptoms compared to placebo.37,38 Other drug therapies that are expected to reach the market in the future include a pipamperone/citalopram combination,

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12 ALABAMA PHARMACY ASSOCIATION | SPRING 2015: CONTINUING EDUCATION 35. Vortioxetine. In: Drug Facts and Comparisons (Facts and Comparisons eAnswers) [AUSHOP Intranet]. St. Louis: Wolt- ers Kluwer Health [Updated Feb 2014]. [cited 4 March 2014]. Available from: http://online.factsandcomparisons.com/ MonoDisp.aspx?monoID=fandc-hcp19108&quick=1059950|5&search=1059950|5&isstemmed=True&NDCmapping=- 1&fromTop=true#firstMatch. 36. Vortioxetine. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Lexi-Comp, Inc. [updated Mar 5, 2014, cited 2014 Mar 6. [about 5 p.]. Available from: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/4720782 37. Mahableshwarkar AR, Jacobsen PL, Chen Y. A randomized, double-blind trial of 2.5 mg and 5 mg vortioxetine (Lu AA21004) versus placebo for 8 weeks in adults with major depressive disorder. Curr Med Res Opin. 2013 Mar;29(3):217-26. 38. Jain R, Mahableshwarkar AR, Jacobsen PL, Chen Y, Thase ME. A randomized, double-blind, placebo-controlled 6-wk trial of the efficacy and tolerability of 5 mg vortioxetine in adults with major depressive disorder. Int J Neuropsychopharmacol. 2013 Mar;16(2):313-21. 39. Gibb A. Pipeline: Major depressive disorder therapeutics. Adis International. [2013 Nov]. [cited 3/4/2014]. [about 2 screens]. Avail- able from: http://www.pmlive.com/pharma_news/pipeline_major_depressive_disorder_therapeutics_521621. 40. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct 1; 170(10): 1134-42. 41. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009 Sep 1;66(5):522-26. 42. Columbia University. Ketamine in the Treatment of Depression. In: ClinicalTrials.gov [internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 March 5]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01558063. NLM identifier: NCT01558063.

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