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Home , Desvenlafaxine, Hydroxybupropion, Levomilnacipran

Savvy Psychopharmacology Web audio at CurrentPsychiatry.com Dr. Resch: How renal disease can alter pharmacotherapy

When to adjust the dosing of psychotropics in patients with renal impairment

Sarah Ward, PharmD, Julius Paul Roberts, DO, William J. Resch, DO, DFAPA, and Christopher Thomas, PharmD, BCPS, BCPP

enal disease can play a large role in Overall, there is minimal informa- altering the of tion about the effects of renal disease on R medications, especially in elimination psychotropic therapy; our goal here is to or clearance and . summarize available data. We have cre- Specifically, renal impairment decreases ated quick reference tables highlighting the plasma protein binding secondary to psychotropics that have renal dosing rec- decreased albumin and retention of urea, ommendations based on manufacturers’ Vicki L. Ellingrod, which competes with medications to bind package inserts. PharmD, FCCP to the protein.1 Department Editor Electrolyte shifts—which could lead to a fatal arrhythmia—are common among First-generation antipsychotics (FGAs). patients with renal impairment. The risk Dosage adjustments based on renal func- can be further increased in this population tion are not required for any FGA, accord- if a patient is taking a medication that can ing to manufacturers’ package inserts. induce arrhythmia. If a drug is primarily Some of these antipsychotics are excreted in excreted by the kidneys, elimination could , but typically as inactive metabolites. be significantly altered, especially if the Although there are no dosage recommen- medication has active metabolites.1 dations based on renal function provided Normal renal function is defined as an by the labeling, there has been concern estimated creatinine clearance (eCrCl) of about the use of some FGAs in patients >80 mL/min. Renal impairment is classi- with renal impairment. Specifically, con- fied as: cerns center around the piperidine pheno- • mild: eCrCl, 51 to 80 mL/min thiazines ( and ) • moderate: eCrCl, 31 to 50 mL/min because of the increased risk of electro- • severe: eCrCl, ≤30 mL/min cardiographic changes and medication- • end-stage renal disease (ESRD): eCrCl, <10 mL/min.2 Practice Points • Renal disease can play a significant role Savvy Psychopharmacology Dr. Ward is a PGY-2 Psychiatric Pharmacy Practice Resident, and Dr. in altering the pharmacokinetics of is produced in partnership Roberts is a Staff Psychiatrist, Chillicothe VAMC, Chillicothe, Ohio. Dr. medications, especially in elimination or with the College Resch is Staff Psychiatrist, OhioHealth, Columbus, Ohio. Dr. Thomas clearance and plasma protein binding. of Psychiatric is Director, PGY-1 and PGY-2 Residency Programs, Clinical Pharmacy and Neurologic Specialist in Psychiatry, Chillicothe VAMC, and Clinical Associate • Most psychotropics can be used safely Pharmacists Professor of , Ohio University College of Osteopathic cpnp.org Medicine, Chillicothe, Ohio. in patients with mild or moderate renal mhc.cpnp.org (journal) Disclosures impairment. The contents of this article do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. • Dosage adjustment and caution should This material is the result of work supported with resources and the be employed when using a psychotropic as Current Psychiatry use of facilities at the Chillicothe Veterans Affairs Medical Center in severity of renal impairment increases. 60 August 2016 Chillicothe, Ohio. Savvy Psychopharmacology

Table 1 Second-generation antipsychotics: Recommended dosage adjustments in renal impairment Mild renal Moderate renal Severe renal Medication impairment impairment impairment ESRD or dialysis Clozapine8 None None Dosage adjustment may be necessary in the setting of significant renal impairment Risperidone9 None None Initial dosage: 0.5 mg twice daily Increase in increments of ≤0.5 mg At a dosage of >1.5 mg twice daily, only increase at interval of ≥1 week Paliperidone10 Initial: 3 mg once 1.5 mg once daily initially Use not daily (maximum (maximum dosage, 3 mg/d) recommended dosage, 6 mg/d) Clinical Point Lurasidone11 None Initial: 20 mg/d (maximum dosage, 80 mg/d) Most SGAs undergo eCrCl: estimated creatinine clearance; ESRD: end-stage renal disease extensive hepatic before , allowing induced arrhythmias in renal disease due The manufacturers’ package inserts for them to be used to electrolyte imbalances.3,4 Additionally, , , , and lur- safely in patients there is case evidence5 that asidone have recommended dosage adjust- antipsychotics could increase a patient’s ments based on renal function (Table 1).8-11 with renal disease risk for hypotension in chronic renal fail- ure. is considered safe in renal . Although ziprasidone disease because <1% of the medication is does not have a recommended renal dos- excreted unchanged through urine.6 age adjustment, caution is recommended because of the risk of electrocardiographic Second-generation antipsychotics (SGAs). changes and potential for medication- Overall, SGAs are considered safe in patients induced arrhythmias in patients with electro- with renal disease. Most SGAs undergo lyte disturbances secondary to renal disease. extensive hepatic metabolism before excre- A single-dosage study of ziprasidone by tion, allowing them to be used safely in Aweeka et al12 demonstrated that the phar- patients with renal disease. macokinetics of ziprasidone are unchanged Sheehan et al7 analyzed the metabo- in patients with renal impairment. lism and excretion of SGAs, evaluating 8 antipsychotics divided into 4 groups: (1) . A small study by Peeters et al13 excretion primarily as an unchanged drug evaluated the pharmacokinetics of asenapine in urine, (2) changed drug in urine, (3) in hepatic and renal impairment and found changed drug in feces, (4) and unchanged no clinically relevant changes in asenapine’s drug in feces. pharmacokinetics among patients with any • Paliperidone was found to be primar- level of renal impairment compared with ily excreted as an unchanged drug in urine. patients with normal renal function. Discuss this article at • Clozapine, , , www.facebook.com/ CurrentPsychiatry , and risperidone all were found . Mallikaarjun et al14 com- to be primarily excreted as a changed drug pleted a small study evaluating the phar- in urine. macokinetics of aripiprazole in patients • Aripiprazole and ziprasidone were with renal impairment. They found that the found to be primarily excreted as a changed pharmacokinetics of aripiprazole in these Current Psychiatry drug in feces. patients is no different than it is in patients Vol. 15, No. 8 61 Savvy Psychopharmacology

with normal renal function who are taking to the package insert, no dosage adjust- aripiprazole. ments are needed.17 No extensive studies have been conducted on or Quetiapine. Thyrum et al15 conducted a sim- , but each should be initiated at ilar study with quetiapine, which showed a reduced dosage and the titration schedule no significant difference detected in the should be prolonged in patients with severe pharmacokinetics of quetiapine in patients renal impairment or ESRD.17,18 with renal impairment. Additionally, que- The plasma concentration of tiapine had no negative effect on patients’ has been noted to be elevated in patients creatinine clearance. with severe renal impairment, and the half- life can increase to nearly 50%.4 Paroxetine . During clinical trials of lurasi- should be initiated at 10 mg/d, and then done in patients with mild, moderate, and titrated slowly in patients with severe renal Clinical Point 19,28 severe renal impairment, the mean Cmax and impairment. The plasma area under the curve was higher compared The pharmacokinetics of are with healthy patients, which led to recom- unchanged in any stage of renal impair- concentration of mended dosage adjustments in patients ment. Patients in active renal dialysis report paroxetine has with renal impairment.11 good tolerability and efficacy.4 been noted to be As mentioned above, renal impairment elevated in patients decreases the protein binding percentage - reuptake of medications. Hypothetically, the greater inhibitors. and its metabolite with severe renal the protein binding, the lower the recom- O-desmethylvenlafaxine () impairment mended dosage in patients with renal are primarily excreted via renal elimination. impairment because the free or unbound Studies have shown that mild renal impair- form correlates with efficacy and toxicity. ment can have an effect on plasma levels Most FGAs and SGAs have the protein- of the drug, and that moderate or severe binding characteristic of ≥90%.16 Although impairment can increase the venlafaxine it seems this characteristic should result in plasma concentration. According to the recommendations to adjust dosage based package insert, a dosage reduction of 50% on renal function, the various pharmaco- is recommended for desvenlafaxine and kinetic studies of antipsychotics have not venlafaxine.20,21 shown this factor to play a role in the manu- No significant pharmacokinetic changes facturers’ recommendations. with have been noted in patients with mild or moderate renal impairment.22 However, duloxetine’s major metabolites, Comorbidity rates of depression in which are excreted renally, have been mea- patients with renal disease range from 14% sured to be as much as 7 to 9 times higher in to 30%, making use of antidepressants in patients with ESRD compared with healthy renal disease common.4 Antidepressants subjects; therefore, it is recommended to primarily are metabolized hepatically and avoid duloxetine in patients with severe excreted renally. Table 217-27 summarizes renal disease.4,22 recommended dosing adjustments for Our review of the literature produced lim- antidepressants. ited recommendations on dosing milnacip- ran and its enantiomer in Selective serotonin reuptake inhibitors. renally impaired patients. The Escitalopram is the (S)-enantiomer of the package insert cautions its use in moderate racemic citalopram, both of renal impairment and recommends a 50% which have been shown to decrease renal dosage reduction to 100 mg/d (50 mg twice clearance in patients with mild or moder- daily) in patients with severe renal impair- Current Psychiatry 62 August 2016 ate renal impairment. However, according ment.23 Dosage recommendations for Savvy Psychopharmacology

Table 2 Antidepressants: Recommended dosage adjustments in renal impairment Mild renal Moderate renal Severe renal Medication impairment impairment impairment ESRD or dialysis Escitalopram17 None None (eCrCl <20 mL/min) No information available Use caution: Start at a reduced dosage and titrate slowly Citalopram18 None None Use caution: Start at a reduced dosage and titrate slowly Paroxetine19 None None Initial dosage: 10 mg/d Maximum dosage: 40 mg/d Clinical Point Venlafaxine20 (GFR 10 to 70 mL/min) Decrease dosage by Decrease dosage by 25% to 50% 50% and withhold TCAs are until dialysis is complete predominantly Desvenlafaxine21 None 50 mg/d (do 50 mg every other day (do not titrate) metabolized not titrate) hepatically, 22 Duloxetine None None (GFR <30 mL/min) glucuronidated, and Avoid use Milnacipran23 None Use caution Decrease dosage Relative then eliminated by 50% contraindication renally Levomilnacipran24 None 80 mg/d 40 mg/d Relative contraindication TCAs25 None Decrease by 50% in geriatric patients Bupropion26,27 (GFR <90 mL/min) 75 mg once daily Consider reducing the dosage or frequency None 150 mg every 3 days eCrCl: estimated creatinine clearance; ESRD: end-stage renal disease; GFR: glomerular filtration rate; TCA: antidepressants

levomilnacipran are 80 mg/d for moderate lites could increase patients’ sensitivity to renal impairment and 40 mg/d for severe side effects of TCAs. Because of concerns impairment. Both agents have relative con- regarding elevated glucuronidated metabo- traindications for ESRD.23,24 lites, it has been proposed to initiate TCAs at a low dosage, titrate slowly, and maintain Tricyclic antidepressants (TCAs) are pre- the lowest effective dosage in patients with dominantly metabolized hepatically, gluc- renal impairment.25 uronidated, and then eliminated renally. , , and nortripty- Monoamine oxidase inhibitors (MAOIs) line have nonspecific package insert recom- and other antidepressants. The package mendations for modified dosing in geriatric inserts of the MAOIs , phen- patients because of an age-related decrease elzine, , and in renal clearance.29-31 Review articles assert provide limited data and dosage recommen- Current Psychiatry that elevated glucuronidated metabo- dations for use in the context of renal impair- Vol. 15, No. 8 63 Savvy Psychopharmacology

Table 3 Mood stabilizers: Recommended dosage adjustments in renal impairment Mild renal Moderate renal Severe renal ESRD or Medication impairment impairment impairment dialysis Lithium41 None None Relative contraindication Lamotrigine44 None None Reduced maintenance dosage may be effective Oxcarbazepine46 None None IR: Initiate at 50% of the usual starting dosage (300 mg/d) and titrate slowly ER: Initiate at 300 mg/d; may be titrated in increments of 300 to 450 mg/d weekly Clinical Point eCrCl: estimated creatinine clearance; ER: extended release; ESRD: end stage renal disease: IR: immediate release Extra vigilance is required when using MAOIs in patients with ment.32-36 Isocarboxazid should not be used use at the first sign of any change in renal disease because in patients with severe renal impairment, renal function; however, monitoring, preven- of an increased risk according to the prescribing information.32 tion, and treatment guidelines for lithium are There are no dosing recommendations for well established after many years of research of dialysis-induced transdermal selegiline in mild, moderate, or and clinical use.39 Lithium’s prescribing hypotension severe renal impairment.37 Extra vigilance is information recommends dosage adjust- required when using MAOIs in patients with ment in mild to moderate renal impairment renal disease because of an increased risk of and lists severe renal impairment and ESRD dialysis-induced hypotension (orthostatic as relative contraindications.40 hypotension is a common adverse effect of A recent study proposes more asser- MAOIs).38 tive use of lithium in patients with renal is primarily metabolized impairment of any severity. Rej et al41 com- hepatically to the pared continued lithium treatment to dis- . Plasma levels of this continuing treatment in geriatric patients metabolite at steady state are reported with chronic renal failure, and reported to be 10 times greater than bupropion’s (1) a statistically insignificant difference in concentration levels in healthy subjects; renal function between groups at 2 years and plasma levels are further increased in mild (2) a “trending decrease” in renal function renal impairment.26 Hydroxybupropion at 5 years in the lithium treatment group. is not dialyzable, which can increase the With closely monitored plasma levels, risk of toxicity with bupropion therapy lithium treatment is considered a workable in patients with renal impairment.3 If treatment for patients with moderate renal bupropion effectively treats depression impairment when mood stabilizer treatment in patients with declining renal function, has been effective.42 specifically severe renal impairment and ESRD, then decreasing the dosage to 150 Lamotrigine and its main glucuronidated mg every 3 days is recommended to lessen metabolite, lamotrigine-2N-glucuronide the risk of toxicity. 27 (L-2-N-G), are primarily excreted renally. In severe renal impairment and ESRD, the L-2- Mood stabilizers N-G levels are elevated but are not pharma- Lithium has the most published literature on cologically active and, therefore, do not affect dosing adjustments with renal impairment. plasma concentration or efficacy of lamotrig- Current Psychiatry 64 August 2016 Many providers are inclined to discontinue ine.43 Although data are limited regarding Savvy Psychopharmacology

the use of lamotrigine in severe renal impair- ment and ESRD, Kaufman44 reported a 17% Related Resources to 20% decrease in concentration after dialy- • Cohen LM, Tessier EG, Germain MJ, et al. Update on psy- sis—suggesting that post-dialysis titration chotropic medication use in renal disease. Psychosomatics. 2004;45(1):34-48. might be needed in these patients. • Baghdady NT, Banik S, Swartz SA, et al. Psychotropic drugs and renal failure: translating the evidence for clinical prac- Oxcarbazepine is metabolized by means tice. Adv Ther. 2009;26(4):404-424. of cytosolic in the to its pri- Drug Brand Names mary pharmacologically active metabolite, Aripiprazole • Abilify Lurasidone • Latuda Asenapine • Saphris Mesoridazine • Serentil 10-monohydroxy, which is further metabo- Bupropion • Wellbutrin Milnacipran • Savella lized via glucuronidation and then renally Citalopram • Celexa • Pamelor Clozapine • Clozaril, Fazaclo Olanzapine • Zyprexa excreted. There are no dosage adjustment Desipramine • Norpramin Oxcarbazepine • Trileptal recommendations for patients with an Desvenlafaxine • Pristiq Paliperidone • Invega eCrCl >30 mL/min.45 Rouan et al46 suggest Duloxetine • Cymbalta Paroxetine • Paxil Clinical Point Escitalopram • Lexapro • Nardil initiating oxcarbazepine at 50% of the rec- Fluoxetine • Prozac Quetiapine • Seroquel Monitoring, ommended dosage and following a longer Haloperidol • Haldol Risperidone • Risperdal Iloperidone • Fanapt Selegiline • EMSAM, Eldepryl prevention, and titration schedule in patients with an eCrCl Imipramine • Tofranil Thioridazine • Mellaril 10 to 30 mL/min. No dosing suggestions Isocarboxazid • Marplan Tranylcypromine • Parnate treatment guidelines Lamotrigine • Lamictal Venlafaxine • Effexor, for severe renal impairment and ESRD Levomilnacipran • Fetzima Effexor XR for lithium are well were provided because of study limitations; Lithium • Eskalith, Lithobid Ziprasidone • Geodon established after however, the general recommendation for many years of research psychotropic agents in patients in a severe stage of renal impairment is dosage reduc- and clinical use tion with close monitoring.46 13. Peeters P, Bockbrader H, Spaans E, et al. Asenapine 41,44,46 pharmacokinetics in hepatic and renal impairment. Clin Table 3 summarizes dosage adjust- Pharmacol. 2011;50(7):471-481. ments for mood stabilizers in patients with 14. Mallikaarjun S, Shoaf SE, Boulton DW, et al. Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole. Clin renal impairment. Pharmacokinet. 2008;47(8):533-542. 15. Thyrum PT, Wong YW, Yeh C. Single-dose pharmacokinetics References of quetiapine in subjects with renal or hepatic impairment. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(4): 1. Levy G. Pharmacokinetics in renal disease. Am J Med. 521-533. 1977;62(4):461-465. 16. Lexi-Drugs. Lexicomp. Hudson, OH: Wolters Kluwer Health, 2. Preskorn SH. Clinically important differences in the Inc. http://online.lexi.com. Accessed May 28, 2015. pharmacokinetics of the ten newer “atypical” antipsychotics: part 3. Effects of renal and hepatic impairment. J Psychiatr 17. Lexapro [package insert]. Forest Pharmaceuticals, Inc.: St. Pract. 2012;18(6):430-437. Louis, MO; 2014. 3. Cohen LM, Tessier EG, Germain MJ, et al. Update on 18. Celexa [package insert]. Forest Pharmaceuticals, Inc.: St. Louis, psychotropic medication use in renal disease. Psychosomatics. MO; 2014. 2004;45(1):34-48. 19. Paxil [package insert]. Research Triangle Park, NC: 4. Baghdady NT, Banik S, Swartz SA, et al. Psychotropic drugs GlaxoSmithKline; 2008. and renal failure: translating the evidence for clinical practice. 20. Effexor [package insert]. Philadelphia, PA: Adv Ther. 2009;26(4):404-424. Pharmaceuticals Inc.; 2010. 5. Sheehan J, White A, Wilson R. Hazards of in 21. Pristiq [package insert]. Philadelphia, PA: Wyeth chronic renal failure. Ir Med J. 1982;75(9):335. Pharmaceuticals Inc.; 2014. 6. Haloperidol [monograph]. In: Micromedex Drugdex [online 22. Cymbalta [package insert]. Indianapolis, IN: Lilly USA, LLC; database]. Greenwood Village, CO: Truven Health Analytics. 2014. Accessed December 17, 2014. 23. Savella [package insert]. St. Louis, MO: Forest Pharmaceuticals, 7. Sheehan JJ, Sliwa JK, Amatniek JC, et al. Atypical Inc.; 2013. metabolism and excretion. Curr Drug Metab. 2010;11(6): 24. Fetzima [package insert]. St. Louis, MO: Forest Pharmaceuticals, 516-525. Inc.; 2014. 8. Clozaril [package insert]. East Hanover, NJ: Novartis 25. Kurella M, Bennett WM, Chertow GM. Analgesia in patients Pharmaceuticals; 2014. with ESRD: a review of available evidence. Am J Dis. 9. Risperdal [package insert]. Titusville, NJ: Janssen 2003;42(2):217-228. Pharmaceuticals; 2014. 26. Wellbutrin [package insert]. Research Triangle Park, NC: 10. Invega [package insert]. Titusville, NJ: Janssen Pharmaceuticals; GlaxoSmithKline; 2014. 2014. 27. Worrall SP, Almond MK, Dhillon S. Pharmacokinetics of 11. Latuda [package insert]. Fort Lee, NJ: Sunovion bupropion and its metabolites in haemodialysis patients Pharmaceuticals; 2013. who smoke. A single dose study. Nephron Clin Pract. 12. Aweeka F, Jayesekara D, Horton M, et al. The pharmacokinetics 2004;97(3):c83-c89. of ziprasidone in subjects with normal and impaired renal 28. Nagler EV, Webster AC, Vanholder R, et al. Antidepressants Current Psychiatry function. Br J Clin Pharmacol. 2004;49(suppl 1):27S-33S. for depression in stage 3-5 chronic kidney disease: a Vol. 15, No. 8 65 This month’s quickpoll% Savvy Psychopharmacology Mr. R, age 35, begins clozapine treatment for treatment-refractory systematic review of pharmacokinetics, efficacy and schizophrenia during his inpatient stay. He has no significant medical safety with recommendations by European Renal Best history. Screening labs and baseline electrocardiogram (ECG) are within Practice (ERBP). Nephrol Dial Transplant. 2012;27(10): 3736-3745. normal limits. Three days after initiating clozapine, Mr. R develops 29. Norpramin. [package insert] Bridgewater, NJ: Sanofi-Aventis with an otherwise normal physical exam and negative review U.S. LLC; 2014. of systems. A repeat ECG is notable only for sinus tachycardia. What is 30. Tofranil [package insert]. Hazelwood, MO: Mallinckrodt Inc.; the best next step? 2014. 31. Pamelor [package insert]. Hazelwood, MO: Mallinckrodt Inc.; 2014. ■ Stop clozapine 32. Marplan [package insert]. Parsippany, NJ: Validus ■ Wait and monitor Pharmaceuticals, LLC; 2012. 33. Nardil [package insert]. New York, NY: Parke-Davis Division of ■ Initiate Pfizer Inc.; 2009. ■ Initiate atenolol 34. EMSAM [package insert]. Morgantown, WV: Mylan Specialty, L.P.; 2014. 35. Eldepryl [package insert]. Morgantown, WV: Somerset See “Rediscovering clozapine: Adverse effects develop— Pharmaceuticals, Inc.; 2009. what should you do now?” pages 40-46,48,49 36. Parnate [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. 37. Culpepper L. Reducing the burden of difficult-to-treat major depressive disorder: revisiting monoamine oxidase inhibitor Visit CurrentPsychiatry.com to answer the Quick Poll therapy. Prim Care Companion CNS Disord. 2013;15(5). doi: and see how your colleagues responded. 10.4088/PCC.13r01515. 38. Tossani E, Cassano P, Fava M. Depression and renal disease. Semin Dial. 2005;18(2):73-81. 39. Young AH, Hammond JM. Lithium in mood disorders: JUNE POLL RESULTS increasing evidence base, declining use? Br J Psychiatry. 2007;191:474-476. 40. Eskalith [package insert]. Research Triangle Park, NC: Ms. B, age 29, reports that fatigue, sadness, and feelings of GlaxoSmithKline; 2003. 41. Rej S, Looper K, Segal M. The effect of serum lithium levels worthlessness have compromised her work and eroded her on renal function in geriatric outpatients: a retrospective friendships. You make a diagnosis of major depressive disorder; longitudinal study. Drugs Aging. 2013;30(6):409-415. prescribe citalopram, 20 mg/d; and refer her for cognitive-behavioral 42. Malhi GS, Tanious M, Das P, et al. The science and practice of lithium therapy. Aust N Z J Psychiatry. 2012;46(3):192-211. therapy. At 2-month follow-up, you notice that Ms. B has gained 10 lb. 43. Lamictal [package insert]. Research Triangle Park, NC: What would you do to address Ms. B’s weight gain? GlaxoSmithKline; 2014. 44. Kaufman KR. Lamotrigine and hemodialysis in bipolar 33% Recommend that she reduce disorder: case analysis of dosing strategy with literature review. portion size at meals and exercise Bipolar Disord. 2010;12(4):446-449. 45. Trileptal [package insert]. East Hanover, NJ: Novartis 45 minutes a day 15% Pharmaceuticals Corporation; 2014. 20% 46. Rouan MC, Lecaillon JB, Godbillon J, et al. The effect of renal Stop citalopram and switch to 33% impairment on the pharmacokinetics of oxcarbazepine and , 10 mg/d, and titrate its metabolites. Eur J Clin Pharmacol. 1994;47(2):161-167. to 20 mg/d 32% 32% Refer her to a nutritionist for 20% education on making healthy diet choices 15% Add bupropion, 100 mg, 3 times a day

suggested reading: MacDaniels JS, Schwartz TL. Current Psychiatry. 2015;15(6):30- 32,35,36,38,39,47,48.

Data obtained via CurrentPsychiatry.com, June 2016