TRIPASS XR تري باس

 

D.C.’s history of nausea from venlafaxine, an alternate SNRI, such as

levomilnacipran or duloxetine, should be initiated. Duloxetine inhibits CYP450 2D6,

and this should be taken into consideration if other medication changes are

considered in the future.

Summary

Depressive episodes have a significant morbidity impact and can result in mortality,

usually via suicide. Treatment has been shown to reduce acute impact and prevent

future episodes. All antidepressants are considered generally equal in regard to

efficacy. Comorbid drug–disease and drug–drug interactions help identify best firstchoice options. Overall, SSRIs are considered the best first choice due to good

tolerability, safety in overdose, and low cost. Of these, sertraline and escitalopram

may have a slight advantage. Previous treatment successes or failures and family

history of medication response are important determining factors when disease and

drug issues are not present. Minimal treatment duration should be 6 months after

remission has been achieved though many patients will require lifelong

pharmacotherapy. Patient education and safety monitoring are critical aspects once

the patient enters into treatment. Outcomes for treatment are predictably beneficial

with improvements in quality of life and reduction of suicidal events.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Cleare A et al. Evidenced based guidelines for treating depressive disorders with antidepressants: a revision of the

2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015;29(5):459–525. (5)

Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA:

American Psychiatric Association. 2010. (10)

Spina E et al. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 2012;26(1):39–67.

(138)

Key Websites

American Psychiatric Association. http://www.psychiatryonline.org.

National Alliance on Mental Illness. http://www.nami.org.

National Institute of Mental Health. http://www.nimh.nih.gov.

COMPLETE REFERENCES CHAPTER 86 DEPRESSIVE

DISORDERS

National Collaborating Centre for Mental Health (UK). Depression: The Treatment and Management of

Depression in Adults (Updated Edition). National Institute for Health and Clinical Excellence: Guidance.

Leicester (UK): British Psychological Society; 2010

Wells KB et al. The functioning and well-being of depressed patients. JAMA. 1989;262:914.

Greenberg PE et al. The economic burden of depression in the United States: how did it change between 1990 and

2000? J Clin Psychiatry. 2003;64:1465.

Kessler RC et al. Prevalence, severity and comorbidity of 12-month DSM-IV disorders in the national comorbidity

survey [published correction appears in Arch Gen Psychiatry. 2005;62:709]. Arch Gen Psychiatry. 2005;62:617.

Cleare A et al. Evidenced based guidelines for treating depressive disorders with antidepressants: a revision of the

2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015;29(5):459–525.

Lieb R et al. Parental major depression and the risk of depression and other mental disorders in offspring: a

prospective-longitudinal community study. Arch Gen Psychiatry. 2002;59:365.

McGuffin P, Katz R. The genetics of depression and manic depressive disorder. Br J Psychiatry. 1989;155:294.

Blehar MC et al. Family and genetic studies of affective disorders. Arch Gen Psychiatry. 1988;45:289.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, (DSM-5). 5th ed.

Arlington, VA: American Psychiatric Association Press; 2013.

Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington, VA: American

Psychiatric Association; 2010.

Cuijpers P et al. Are psychological and pharmacologic interventions equally effective in the treatment of adult

depressive disorders? A meta-analysis of comparative studies. J Clin Psychiatry. 2008;69:1675.

Schildkraut JJ. Neuropsychopharmacology and the affective disorders. N EnglJ Med. 1969;281:302.

Maas JW. Biogenic amines and depression. Arch Gen Psychiatry. 1975;32:1357.

Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog

Neuropsychopharmacol Biol Psychiatry. 2013;45:54–63.

Kohler S et al. The serotonergic system in the neurobiology of depression: relevance for novel antidepressants. J

Psychopharmacol. 2016;30(1):13–22.

Richelson E. Multi-modality: a new approach for the treatment of major depressive disorder. Int J

Neuropsychopharmacol. 2013;16:1433–1442.

Artigas F et al. Mechanism of action of antidepressants. Psychopharmacol Bull. 2002;36(suppl 2):123–132.

Charney DS et al. Receptor sensitivity and the mechanisms of action of antidepressant treatment. Arch Gen

Psychiatry. 1981;381:1160.

Risch SC, Nemeroff CB. Neurochemical alterations of serotonergic neuronal systems in depression. J Clin

Psychiatry. 1992;53:3.

Kramer MS et al. Distinct mechanism for antidepressant activity by blockade of central substance p receptors.

Science. 1998;281:1640.

Gold PW et al. New insights into the role of cortisol and the glucocorticoid receptor in severe depression. Biol

Psychiatry. 2002;52:381.

Nemeroff CB. New directions in the development of antidepressants: the interface of neurobiology and

psychiatry. Hum Psychopharmacol. 2002;17:13.

Valdez GR. Development of CRF1 receptor antagonists as antidepressants and anxiolytics. Progress to date.

CNS Drugs. 2006;201(11):887–896.

Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry.

2007;64:327.

Nemeroff CB, Evans DL. Thyrotropin-releasing hormone (TRH), the thyroid axis, and affective disorder. Ann N

Y Acad Sci. 1989;553:304.

Mitchell J et al. Institute for Clinical Systems Improvement. Adult depression in primary care. Updated

September 2013.

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatr Res.

2015;229:27–36.

Duval F et al. Chronobiological hypothalamic-pituitary-thyroid axis status and antidepressant outcome in major

depression. Psychoneuroendocrinology. 2015;59:71–80.

Carroll BJ et al. Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand. 2007;115(S433):90–

103.

Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosom Med. 1999;5:698.

Belanoff JK et al. Anopenlabeltrialof C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry.

2002;5:386.

Lee AL et al. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord.

2002;4:117.

Agarwal N et al. Update on the use of MR for assessment and diagnosis of psychiatric diseases. Radiology.

2010;255(1):23–41.

Sarubin N et al. Impact on cortisol and antidepressant efficacy of quetiapine and escitalopram in depression.

Psychoneuroendocrinology. 2014;39:141–151.

Karlovic d et al. Serum concentrations of CRP, IL-6, TNF-alpha and cortisol in major depressive disorder with

melancholic or atypical features. Psychiatry Res. 2012;198:74–80.

Lotrich FE. Inflammatory cytokine-associated depression. Brain Res. 2015;1617:113–125.

Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive

disorder. Mol Psychiatry. 2010;15:473–500.

Serretti A et al. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association

with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry. 2007;12:247.

Horstmann S, Binder EB. Pharmacogenomics of antidepressant drugs. Pharmacol Ther. 2009;124:57–73.

Fabbri C, Serretti A. Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical

applications. Curr Psychiatry Rep. 2015;17:50.

George MS et al. SPECT and PET imaging in mood disorders. J Clin Psychiatry. 1993;54:6.

Nemeroff CB. The neurobiology of depression. Sci Am. 1998;278:42.

Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based

algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193.

Cole J et al. Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging

studies. J Affect Disord. 2011;134:483–487.

Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56.

Beck AT et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561.

Zung WW. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63.

Montgomery SA, Asberg M. New depression scale designed to be sensitive to change. Br J Psychiatry.

1979;134:382.

Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol

Meas. 1977;1:385.

Kroenke K et al. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606.

Rush AJ et al. The 16-item Quick Inventory of Depressive Symptomatology (QIDS), Clinician Rating (QIDS-C),

and Self-Report (QIDS-SR): a psychometric evaluation in patients with chronic major depression [published

correction appears in Biol Psychiatry. 2003;54:585]. Biol Psychiatry. 2003;54:573.

Siu AL; the USPSTF. Screening for depression in adults. US Preventative Services Task Force recommendation

statement. JAMA. 2016;315(4):380–387.

Arnow BA, Constantino MJ. Effectiveness of psychotherapy and combination treatment for chronic depression. J

Clin Psychol. 2003;59:893.

UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic

review and meta-analysis. Lancet. 2003;361(9360):799–808.

Devanand DP et al. Electroconvulsive therapy in the treatment-resistant patient. Psychiatr Clin North Am.

1991;14:905.

Cusin C, Dougherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biol

Mood Anxiety Disord. 2012;2:14.

Shapira B et al. Cost and benefit in the choice of ECT schedule. Br J Psychiatry. 1998;172:44.

Kellner CH et al. Continuation electroconvulsive therapy vs. pharmacotherapy for relapse prevention in major

depression: a multisite study from the consortium for research in electroconvulsive therapy (CORE). Arch Gen

Psychiatry. 2006;63:1337.

Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55:187–199.

Rossi S et al. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic

stimulation in clinical practice and research. Clin Neurophysiol. 2009;120:208–239.

Martin JL et al. Transcranial magnetic stimulation for treating depression. Cochrane Database Syst Rev. 2003;

(3):CD003387.

Janicak PG et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a

comprehensive summary of safety experience from acute exposure, extended exposure, and during

reintroduction treatment. J Clin Psychiatry. 2008;69:222.

Groves DA, Brown VJ. Vagal nerve stimulation: a review of its applications and potential mechanisms that

mediate its clinical effects. Neurosci Biobehav Rev. 2005;29:493.

Gross F, Gysin F. Phototherapy in psychiatry: clinical update and review of indications. Encephale. 1996;22:143.

Lawlor DA, Hopker SW The effectiveness of exercise as an intervention in the management of depression:

systematic review and meta-regression analysis of randomized controlled trials. BMJ. 2001;322:763.

Brene S et al. Running is rewarding and antidepressive. Physiol Behav. 2007;92:136.

Carlson LE et al. Mindfulness-based stress reduction in relation to quality of life in breast, mood, symptoms of

stress and levels of cortisol, dehydroepiandrosterone and melatonin in breast cancer and prostate cancer

outpatients. Psychoneuroendocrinology. 2004;29:448.

Cipriani A et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multipletreatments meta-analysis. Lancet. 2009;373:746.

Gartlehner G et al. Comparative benefits and harms of second-generation antidepressants for treating major

depressive disorder. An updated meta-analysis. Ann Intern Med. 2011;155:772–785.

Spina E et al. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an

update. Clin Ther. 2008;30(7):1206–1227.

Taylor MJ et al. Early onset of selective serotonin reuptake inhibitor antidepressant action:systematic review and

meta-analysis. Arch Gen Psychiatry. 2006;63:1217.

Dubovsky SL. Beyond the serotonin reuptake inhibitors: rationale for the development of new serotonergic

agents. J Clin Psychiatry. 1994;55(Suppl):34.

Vogel GW et al. Drug effects on REM sleep and on endogenous depression. Neurosci Biobehav Rev.

1990;14:49.

Gregorian RS et al. Antidepressant-induced sexual dysfunction. Ann Pharmacother. 2002;36:1577.

Prabhaker D, Balon R. How do SSRIs cause sexual dysfunction? Curr Psychiatr. 2010;9(12):30–34.

Casper RC et al. Somatic symptoms in primary affective disorder: presence and relationship to the classification

of depression. Arch Gen Psychiatry. 1985;42:1098.

Shen WW, Hsu JH. Female sexual side effects associated with selective serotonin reuptake inhibitors: a

descriptive clinicalstudy of 33 patients. Int J Psychiatry Med. 1995;25:239.

Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J

Psychiatry. 1995;152:1514.

Labbate LA, Pollack MH. Treatment of fluoxetine-induced sexual dysfunction with bupropion: a case report. Ann

Clin Psychiatry. 1994;6:13.

Ashton AK, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J

Clin Psychiatry. 1998;59:112.

Kennedy SH et al. Combining bupropion SR with venlafaxine, paroxetine or fluoxetine: preliminary report on

pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry. 2002;63:181.

Demyttenaere K, Jaspers L. Bupropion and SSRI-induced side effects. J Psychopharmacol. 2008;22(7):792–804.

Woodrum ST, Brown CS. Management of SSRI-induced sexual dysfunction. Ann Pharmacotherapy.

1998;32:1209–1215.

Nurnberg HG et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil. JAMA.

2003;289:56.

Segraves RT et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants. J Clin

Psychopharmacol. 2007;27(1):62–66.

Shrivastava RK et al. Amantadine in the treatment of sexual dysfunction associated with selective serotonin

reuptake inhibitors. J Clin Psychopharmacol. 1995;15:83.

Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin re-uptake inhibitors.

Depression. 1994;2:109.

Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open-label trial of yohimbine. J Clin Psychiatry.

1992;53:119.

Michelson D et al. Female sexual dysfunction associated with antidepressant administration: a randomized,

placebocontrolled study of pharmacologic intervention. Am J Psychiatry. 2000;157:239.

Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther.

1998;24:139.

Gelenberg AJ et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry.

2000;61(5):356–360.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Delgado PL et al. Treatment strategies for depression and sexual dysfunction. J Clin Psychiatry. 1999;17:15.

Gunnell D et al. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: a meta-analysis of drug

company data from placebo controlled, randomized controlled trials submitted to the MHRA’s safety review.

BMJ. 2005;330:385–390.

Isacsson G, Rich CL. Antidepressant drugs and the risk of suicide in children and adolescents. Pediatr Drugs.

2014;16:115–122.

Ferguson JM. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin

Psychiatry. 2001;3:22–27.

Modi S, Lowder D. Medications for migraine prophylaxis. Am Fam Phys. 2006;73(1):72–78.

Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27:1295–1230.

Vida S, Looper K. Precision and comparability of adverse event rates of newer antidepressants. J Clin

Psychopharmacol. 1999;19:416.

Marcy TR, Britton ML. Antidepressant-induced sweating. Ann Pharmacother. 2005;39:748–752.

Mercadante S. Hyoscine in opioid-induced sweating. J Pain Symptom Manage. 1998;15:214.

Romanelli F et al. Possibleparoxetine-inducedbruxism. Ann Pharmacother. 1996;30:1246.

Ellison JM, Stanziani P. SSRI-associated nocturnal bruxism in four patients. J Clin Psychiatry. 1993;54:432.

Rugh JD, Harlan J. Nocturnal bruxism and temporomandibular disorders. Adv Neurol. 1988;49:329.

Kirby D, Ames D. Hyponatremia and selective serotonin reuptake inhibitors in elderly patients. Int J Geriatr

Psychiatry. 2001;16:484.

Arinzon ZH et al. Delayed recurrent SIADH associated with SSRIs. Ann Pharmacother. 2002;36:1175.

Leo RJ. Movement disorders associated with selective serotonin reuptake inhibitors. J Clin Psychiatry.

1996;57:449.

Caley CF. Extrapyramidal reactions and the selective serotonin-reuptake inhibitors. Ann Pharmacother.

1997;31:1481–1489.

Lane RM. SSRI-Induced extrapyramidal side-effects and akathisia: implications for treatment. J

Psychopharmacol. 1998;12(2):192–214.

Levine LR et al. Use of a serotonin re-uptake inhibitor, fluoxetine, in the treatment of obesity. Int J Obes.

1987;11(Suppl 3):185.

Fava M et al. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with

long-term treatment. J Clin Psychiatry. 2000;61:863–867.

Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding. BMJ. 2005;331:529.

Anglin R et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without

concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol.

2014;109:811–819.

Vidal X et al. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by

antidepressants: a case-controlstudy. Drug Saf. 2008;31:159.

Lewis JD et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper

gastrointestinal toxicity. Pharmacoepidemiol Drug Saf. 2008;17:328.

Depression Guideline Panel. Rockville, MD: Agency for Health Policy and Research, US Dept of Health and

Human Services; 1993.

Felice D et al. When aging meets the blues: are the current antidepressants effective in depressed aged

patients? Neurosci Biobehav Rev. 2015;55:478–497.

Warner CH et al. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74:449–457.

Baldessarini RJ et al. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J

Psychiatry. 2010;167:934.

Davies S et al. Depression, suicide, and the nationalservice framework. BMJ. 2001;322:1500–1501.

Judd LL. The clinical course of unipolar major depressive disorders. Arch Gen Psychiatry. 1997;54:989.

Nonacs R, Cohen LS. Depression during pregnancy: diagnosis and treatment options. J Clin Psychiatry.

2002;63:24.

Cohen LS et al. Relapse of major depression during pregnancy in women who maintain or discontinue

antidepressant treatment [published correction appears in JAMA. 2006;296:170]. JAMA. 2006;295:499.

Chaudron LH. Complex challenges in treating depression during pregnancy. Am J Psychiatry. 2013;170:12–20.

Louik C et al. First-trimester use of selective serotonin reuptake inhibitors and the risk of birth defects. N Engl J

Med. 2007;356:2675.

Alwan S et al. Use of serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med.

.

.

.

.

.

.

.

.

.

.

136.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

151.

.

.

.

2007;356:2684.

Berard A et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the

importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80:18.

Laine K et al. Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic

symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry.

2003;60:720.

Wisner KL et al. Does fetal exposure to SSRIs or maternal depression impact infant growth? Am J Psychiatry.

2013;170:485–493.

Einarson A et al. Rates of spontaneous and therapeutic abortions following use of antidepressants in pregnancy:

results from a large prospective database. J Obstet Gynaecol Can. 2009;31:452.

O’Connor E et al. Primary care screening for and treatment of depression in pregnant and postpartum women.

Evidence report and systematic review for the US Preventative Services Task Force. JAMA.

2016;315(4):388–406.

Yonkers KA et al. The management of depression during pregnancy: a report from the American Psychiatric

Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31:403.

Gentile S. The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf. 2005;28(2):138–152.

Spigstet O, Hagg S. Excretion of psychotropic drugs into breast milk: pharmacokinetic overview and therapeutic

implications. CNS Drugs. 1998;9:111.

Wisner KL et al. Serum sertraline and n-desmethylsertraline levels in breast-feeding mother-infant pairs. Am J

Psychiatry. 1998;155:690.

Greenblatt DJ et al. Human cytochromes and some new antidepressants: kinetics, metabolism and drug

interactions. J Clin Psychopharmacol. 1999;19(5 Suppl 1):23S.

Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with

emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl

1):1–21.

Preskorn SH et al. Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6

function in healthy volunteers. J Clin Psychopharmacol. 2007;27(1):28–34.

Spina E et al. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 2012;26(1):39–67.

Jefferson JW, Griest JH. Brusselsprouts and psychopharmacology: understanding the cytochrome P450 system.

Psychiatr Clin North Am. 1996;3:205.

Igbal MM et al. Overview of serotonin syndrome. Ann Clin Psychiatr. 2012;24(4):310–318.

Graber MA et al. Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann Pharmacother.

1994;28:732.

Iruela LM et al. Toxic interaction of S-adenosylmethionine and clomipramine. Am J Psychiatry. 1993;150:522.

Lantz MS et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol.

1999;12:7.

Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148:705.

Nierenberg AA et al. Trazodone for antidepressant associated insomnia. Am J Psychiatry. 1994;151:1069.

Wilson SJ et al. British Association for Psychopharmacology consensus statement on evidence-based treatment

of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;1–25.

Rush AJ et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment

steps: a STAR*D report. Am J Psychiatry. 2006;163:1905.

Paykel ES et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med.

1995;25:1171.

Gibson TB et al. Cost burden of treatment resistance in patients with depression. Am J Manag Care.

2010;16:370.

Brown WA, Harrison W. Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant

to another? J Clin Psychiatry. 1995;56:30.

Thase ME et al. Citalopram treatment of paroxetine intolerant patients. Depress Anxiety. 2002;16:128.

Calabrese JR et al. Citalopram treatment of fluoxet-ineintolerant depressed patients. J Clin Psychiatry.

2003;64:562.

Rush AJ et al. Bupropion-SR, sertraline or venlafaxine-XR after failure of SSRIs for depression. N EnglJ Med.

2006;354:1231.

Kamath J, Handratta V. Desvenlafaxine succinate for major depressive disorder: a critical review of the

evidence. Expert Rev Neurother. 2008;8:1787.

.

.

.

.

.

.

.

.

.

.

.

.

167.

.

.

.

.

.

.

.

.

.

.

.

.

180.

Bymaster FP et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine

transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.

Neuropsychopharmacology. 2001;25:871–880.

Auclair AL et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of

depression and anxiety. Neuropharmacology. 2013;70:338–347.

Deecher DC et al. Desvenlafaxine succinate: a new serotonin and norepinephrine reuptake inhibitor. J

Pharmacol Exp Ther. 2006;318(2):657–665.

Nichols AI et al. Pharmacokinetics, pharmacodynamics, and safety of desvenlafaxine, a serotoninnorepinephrine reuptake inhibitor. J Bioequiv Availab. 2013;5(1):22–30.

Palmer EC et al. Levomilnacipran: as serotonin-norepinephrine reuptake inhibitor for the treatment of major

depressive disorder. Ann Pharmacother. 2014:48(8):1030–1039.

Thase ME. Effect of venlafaxine on blood pressure: a meta-analysis of original data from 3744 patients. J Clin

Psychiatry. 1998;59:502–508.

Wernicke J et al. An evaluation of the cardiovascular safety profile of duloxetine. Findings from 42 placebocontrolled studies. Drug Saf. 2007;30(5):437–455.

Thase ME et al. Effects of desvenlafaxine on blood pressure in patients treated for major depressive disorder: a

pooled analysis. Curr Med Res Opin. 2015;31(4):809–820.

Liebowitz MR et al. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult

outpatients with major depressive disorder. J Clin Psychiatry. 2007;68:1663–1672.

Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety and tolerability of the antidepressants

vilazodone, levomilnacipran and vortioxetine. Expert Opin Pharmacother. 2014;15(17):2525–2542.

McIntyre RS et al. The hepatic safety profile of duloxetine: a review. Expert Opin Drug Metab Toxicol.

2008;4(3):281–285.

Dawson LA. The discovery and development of vilazodone for the treatment of depression: a novel

antidepressant or simply another SSRI? Expert Opin Drug Disc. 2013;8(12):1529–1539.

Citrome L. Vortioxetine for major depressive disorder: an indirect comparison with duloxetine, escitalopram,

levomilnacipran, sertraline, venlafaxine, and vilazodone, using nuber need to harm, and likelihood to be helped or

harmed. J Affect Disord. 2016;196:225–233.

Wang G et al. Comparison of vortioxetine versus venlafaxine XR in adults in Asia with major depressive

disorder: a randomized, double-blind study. Curr Med Res Opin. 2015;31(4):785–794.

Mahableshwarker AR et al. A randomized, double-blind, duloxetine-referenced study comparing efficacy and

tolerability of 2 fixed doses of vortioxetine in the acute treatment of adults with MDD. Psychopharmacology

(Berl). 2015;232:2061–2070.

Boulenger JP et al. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, doubleblind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major

depressive disorder. Int Clin Psychopharmacol. 2014;29(3):138–149.

Boinpally R et al. Influence of CYP3A4 induction/inhibition on the pharmacokinetics of vilazodone in healthy

subjects. Clin Ther. 2014;36(11):1638–1649.

Pearce EF, Murphy JA. Vortioxetine for the treatment of depression. Ann Pharmacother. 2014;48(6):758–765.

Ascher JA et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry.

1995;56:395.

Jain AK et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res.

2002;10:1049.

Alvarez W, Pickworth KK. Safety of antidepressant drugs in the patient with cardiac disease: a review of the

literature. Pharmacotherapy. 2003;23:754.

Roose SP et al. Cardiovascular effects of bupropion in depressed patients with heart disease. Am J Psychiatry.

1991;148:512.

De Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission [published

correction appears in Int Clin Psychopharmacol. 1996;11:153]. Int Clin Psychopharmacol. 1995;10:19.

Wheatley DP et al. Mirtazapine: efficacy and tolerability in comparison with fluoxetine in patients with moderate

to severe major depressive disorder. J Clin Psychiatry. 1998;59:306.

Watanabe N et al. Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major

depression:systematic review and meta-analysis. J Clin Psychiatry. 2008;69(9):1404–1415.

Versiani M et al. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. CNS

Drugs. 2005;19(2):137–146.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Guelfi JD et al. Mirtazapine versus venlafaxine in hospitalized severely depressed patients with melancholic

features. J Clin Psychopharmacol. 2001;21:425.

Preston TC, Shelton RC. Treatment resistant depression: strategies for primary care. Curr Psychiatry Rep.

2013;15;370.

Ferguson JM et al. Reemergence of sexual dysfunction in patients with major depressive disorder: double blind

comparison of nefazodone and sertraline. J Clin Psychiatry. 2001;62:24–29.

Stahl S. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14(10):536–546.

Sheehan DV et al. Extended-release trazodone in major depressive disorder: a randomized, double-blind,

placebo-controlled study. Psychiatry. 2009;6(5):20–33.

Greene DS, Barbhaiya RH. Clinical pharmacokinetics of nefazodone. Clin Pharmacokinet.1997;33(4):260–275.

MacGillivray S et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic

antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ.

2003;326:1014.

Katon W et al. Adequacy and duration of antidepressant treatment in primary care. Med Care. 1992;30:67.

Sclar D et al. Antidepressant pharmacotherapy: economic outcomes in a health maintenance organization. Clin

Ther. 1994;16:715.

Tran PV et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin

Psychopharmacol. 2003;23:78–86.

Rabkin JG et al. Adverse reactions to monoamine oxidase inhibitors. Part II: treatment correlates and clinical

management. J Clin Psychopharmacol. 1985;5:2.

Glassman AH. Cardiovascular effects of tricyclic antidepressants. Annu Rev Med. 1984;35:503.

Cassem N. Cardiovascular effects of antidepressants. J Clin Psychiatry. 1982;43:22.

Freyschuss U et al. Circulatory effects in man of nortriptyline, a tricyclic antidepressant drug. Pharmacologia

Clin. 1970;2:68.

Glassman AH et al. Sertraline treatment of major depression in patients with acute MI or unstable angina

[published correction appears in JAMA. 2002;288:1720]. JAMA. 2002;288:701.

Sauer WH et al. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation. 2001;104:1894.

Serebrauny VL et al. Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary

artery disease. Am J Cardiol. 2001;87:1398.

Bigger JT, Jr et al. Cardiac antiarrhythmic effect of 5 imipramine hydrochloride. N EnglJ Med. 1977;296:206.

Giardina EG, Bigger JT, Jr. Antiarrhythmic effect of imipramine hydrochloride inpatients with ventricular

premature complexes with psychological depression. Am J Cardiol. 1982;50:172.

Muir WW et al. Effects of tricyclic antidepressant drugs on the electrophysiological properties of dog Purkinje

fibers. J Cardiovasc Pharmacol. 1982;4:82.

Roose SP et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease.

JAMA. 1998;279:287.

Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin

Pract. 2005;12:1435–1440.

Castano-Monsalve B. Antidepressants in epilepsy. Rev Neurol. 2013;57(3):117–122.

Warnock JK, Morris DW. Adverse cutaneous reactions to antidepressants. Am J Clin Dermatol. 2002;3(5):329–

339.

Zisook S. A clinical overview of monoamine oxidase inhibitors. Psychosomatics. 1985;26:240.

McGrath PJ et al. A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical

depression. Am J Psychiatry. 2000;157:344.

Haefely W et al. Biochemistry and pharmacology of moclobemide, a prototype RIMA. Psychopharmacology

(Brel). 1992;106(Suppl):S6.

Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal

system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003;64:208–

214.

Robinson DS, Amsterdam JD. The selegiline transdermal system in major depressive disorder: a systematic

review of safety and tolerability. J Affect Disord. 2008;105:15–23.

Murphy DL et al. Monoamine oxidase-inhibiting antide-pressants: a clinical update. Psychiatr Clin North Am.

1984;7:549.

Kronig MH et al. Blood pressure effects of phenelzine. J Clin Psychopharmacol. 1983;3:307.

Salzman C. Clinical guidelines for the use of antidepressant drugs in geriatric patients. J Clin Psychiatry.

.

.

.

.

.

.

.

.

.

.

.

.

225.

.

.

.

.

.

.

232.

.

.

.

.

.

.

.

.

1985;46(10, pt 2):38.

Mallinger AG et al. Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to

cardiovascular effects. Clin Pharmacol Ther. 1986;40:444.

Robinson DS et al. Clinical pharmacology of phenelzine. Arch Gen Psychiatry. 1978;35:629.

Mitchell JE, Popkin MK. Antidepressant drug therapy and sexual dysfunction in men: a review. J Clin

Psychopharmacol. 1983;3:76.

Zhou X et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant

depression:systematic review and network meta-analysis. J Clin Psychiatry. 2015;76(4):e487–e498.

McIntyre RS et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach.

J Affect Disord. 2014;156:1–7.

Rothschild A. Challenges in the treatment of major depressive disorder with psychotic features. Schizophr Bull.

2013;39(4):787–796.

Bauer M et al. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled trials

[published correction appears in J Clin Psychopharmacol. 2000;20:287]. J Clin Psychopharmacol. 1999;119:427.

Altshuler LL et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and

meta-analysis of the literature. Am J Psychiatry. 2001;158:1617.

Nierenberg AJ et al. A comparison of lithium and T3 augmentation following two failed medication treatments

for depression: a STAR-D report. Am J Psychiatry. 2006;163:1484.

Shelton RC et al. Therapeutic options for treatment-resistant depression. CNS Drugs. 2010;24:131.

Centers for Disease Control and Prevention. Mental health surveillance among children-United States, 2005-

2011. MMWR. 2013;62(suppl 2):1–39.

Choe CJ et al. Depression. Child Adolesc Psychiatr Clin N Am. 2012;21:807–829.

Hetrick SE et al. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and

adolescents. Cochrane Database Syst Rev. 2007;3:art no. CD004851.

Hetrick SE et al. Newer generation antidepressants for depressive disorders in children and adolescents.

Cochrane Database Syst Rev. 2012;11:art no. CD004851.

American Academy of Child and Adolescent Psychiatry Official Action. Practice parameter for the assessment

and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry .

2007;46(11):1503–1526.

Cheung AH et al. Guidelines for adolescent depression in primary care (GLAD-PC): II. Treatment and ongoing

management. Pediatrics. 2007;120(5):e1313–e1326.

Wagner KD et al. A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of

pediatric depression. J Amer Acad Child Adolesc Psychiatry. 2006;45(3):280–288.

Hazell P, Mirzaie M. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev.

2013;6:CD002317.

Bridge JA et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric

antidepressant treatment. A meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683–1696.

Schneeweiss S et al. Comparative safety of antidepressant agents for children and adolescents regarding suicidal

acts. Pediatrics. 2010;125(5):876–888.

Isacsson G, Ahlner J. Antidepressants and the risk of suicide in young persons-prescription trends and

toxicological analyses. Acta Psychiatr Scand. 2014;129:296–302.

Worsening depression and suicidality in patients being treated with antidepressants. U.S. Food and Drug

Administration Web site.

http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM173233.pdf. Accessed

April 24, 2016.

Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and

their combination for adolescents with depression. Treatment for adolescents with depression study (TADS)

randomized controlled trial. JAMA. 2004;292:807–820.

Shanmugham B et al. Evidence-based pharmacologic interventions for geriatric depression. Psychiatr Clin North

Am. 2005;28:821–835.

Juurlink D et al. Medical illness and the risk of suicide in the elderly. Arch Intern Med. 2004;164:1179–1184.

Reding M et al. Depression in patients referred to a dementia clinic: a three year prospective study. Arch

Neurol. 1985;42:894.

Meyers BS, Bruce ML. The depression-dementia conundrum. Arch Gen Psychiatry. 1998;55:102.

Green RC et al. Depression as a risk factor for Alzheimer disease. Arch Neurol. 2003;60:753.

.

.

.

.

.

.

247.

.

.

.

.

.

Cummings JL. Dementia and depression: an evolving enigma. J Neuropsychiatry Clin Neurosci. 1989;1:236.

Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann

Pharmacother. 2006;40:1618–1622.

Asberg M et al. Relationship between plasma level and therapeutic effect of nortriptyline. BMJ. 1971;3:331.

Glassman AH et al. Clinical implications of imipramine plasma levels for depressive illness. Arch Gen

Psychiatry. 1977;34:197.

Nelson JC et al. Desipramine plasma concentrations and antidepressant response. Arch Gen Psychiatry.

1982;39:1419.

Ziegler VE et al. Amitriptyline plasma levels and therapeutic response. Clin Pharmacol Ther. 1976;19:795.

Moyes IC et al. Plasma levels and clinical improvement—a comparative study of clomipramine and amitriptyline

in depression. Postgrad Med J. 1980;56(Suppl 1):127.

Robinson DS et al. Plasma tricyclic drug levels in amitriptyline-treated depressed patients. Psychopharmacology.

1979;63:223.

The use of laboratory tests in psychiatry: tricyclic antidepressants—blood level measurements and clinical

outcome. An APA Task Force Report. Am J Psychiatry. 1985;142(2):155–162.

Linder MW, Keck PE, Jr. Standards of laboratory practice: antidepressant drug monitoring. Clin Chem.

1998;44:1073.

Robinson MJ et al. Depression and pain. Front Biosci (Landmark Ed). 2009;14:5031–5051.

Rijavec N, Grubic VN. Depression and pain: often together but still a clinical challenge—a review. Psychiatr

Danub. 2012;24(4):346–352.

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Bipolar disorder is a chronic progressive illness that occurs in

approximately 4% of the population. It is characterized by recurrent

mood episodes of mania and depression. Life stressors, substance use,

treatment non-adherence, and medications are common precipitants of

these mood episodes.

Case 87-1 (Questions 1–3)

Manic episodes are characterized by elevated mood, irritability,

increased goal-directed activity, inflated self-esteem, poor judgment, and

excessive motor activity.

Case 87-1 (Question 1),

Case 87-2 (Question 1)

Depressive episodes of bipolar share the same diagnostic criteria as

major depressive disorder, including depressed mood, decreased

interest, feelings of worthlessness, diminished ability to concentrate, and

recurrent thoughts of death.

Case 87-7 (Question 1)

Valproate, lithium, or atypical antipsychotics are appropriate first-line

treatments for acute mania. Depending on the severity of symptoms,

these agents may be used alone or in combination.

Case 87-1 (Questions 4, 5),

Case 87-2 (Question 1),

Case 87-5 (Question 2),

Case 87-6 (Question 1)

Lithium, lamotrigine, quetiapine, lurasidone, or the combination of these

agents is appropriate treatments for bipolar depression.

Case 87-7 (Question 1)

Maintenance treatment of bipolar disorder is imperative to prevent

disease progression. The standard of practive is to continue the acutephase treatment with gradualsimplification toward monotherapy, if

possible, with lithium, lamotrigine, valproate, or atypical antipsychotics.

Case 87-5 (Question 1),

Case 87-8 (Questions 1, 2)

Medications used to treat bipolar disorder have a wide range of adverse

effects that may impact adherence. The history of response, patient

preference, and long-term tolerability profile are important

considerations when selecting an agent. Therapeutic blood level

monitoring, as well as laboratory monitoring for adverse effects, is

commonly required for certain medications.

Case 87-1 (Questions 6–8),

Case 87-2 (Questions 1–8),

Case 87-3 (Questions 1, 2),

Case 87-4 (Questions 1, 2)

Non-pharmacologic treatments including electroconvulsive therapy

(ECT) and herbalsupplements are important considerations for the

treatment of bipolar disorder.

Case 87-8 (Questions 3, 4)

INTRODUCTION

Bipolar disorder (BD), once known as manic depression, is a severe life-threatening

psychiatric condition that is commonly misdiagnosed and too often insufficiently

treated.

1,2 BD is associated with high rates of healthcare utilization, suicidal

behavior, and use of public assistance.

3 The global burden of BD is immense,

exceeding many chronic diseases including human immunodeficiency virus, diabetes

mellitus, and asthma.

4

Epidemiology

Using DSM-IV-TR criteria, the 12-month prevalence of bipolar I disorder is

estimated to be 0.6%; bipolar II disorder is marginally more common at 0.8%.

5 The

prevalence rate for the bipolar spectrum of illnesses, which include bipolar I,

bipolar II, and subthreshold BD (i.e., Bipolar Disorder Not Otherwise Specified

[NOS]), is 4.4%.

6 Bipolar I and II are more common in women than in men, whereas

subthreshold illness predominates in men.

6 The familial nature of BD has been well

established with an

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p. 1835

11-fold increased risk in first-degree relatives.

7 Twin studies add further support to

the genetic linkage. Goodwin and Jamison reported a 63% concordance rate (rate of

illness in co-twin of affected proband) for monozygotic twins compared with 13%

for dizygotic twins.

7

The estimated total U.S. economic burden of BD between 1991 and 2009 was

reported to be $151 billion.

8 Direct costs, such as hospitalization, outpatient visits,

and medications, accounted for 20% of the total. The remaining 80% was attributable

to indirect costs such as lost productivity by patients and caregivers.

The mean age of onset of symptoms for the bipolar spectrum of illnesses is 21

years.

6 Bipolar I is the earliest in onset at age 18, compared with bipolar II at age 20

and subthreshold BD occurring at age 22.

6 Approximately 20% to 30% of new cases

occur in children between 10 and 15 years old.

9,10 Late-life onset of BD is rare. After

age 60, there is a sharp reduction in the new onset of BD; therefore, a presentation of

mania at this age should alert the clinician to an underlying medical problem as the

possible cause.

11

Patients may present initially with any affective episode, but it is important to note

that 75% of patients report having had multiple episodes of depression before the

development of a manic episode.

9 Not surprisingly, misdiagnosis (primarily as major

depressive disorder) is common, occurring in roughly 70% of patients.

9 By some

accounts, one in four patients visit as many as five physicians before an accurate

diagnosis is made. A significant contribution to misdiagnosis is the underreporting of

manic symptoms, which are not considered to be particularly problematic by

patients.

9

BD is a recurrent illness; single episodes of mania, unrelated to BD, occur in

fewer than 10%.

12 Most patients with BD suffer multiple episodes of mania,

hypomania, or depression separated by periods of euthymia (stable mood) throughout

the course of their lives. In the majority, mania occurs just before or immediately

after a depressive episode.

12 There may be a 5- to 10-year period from the onset of

illness until the first hospitalization or diagnosis of BD.

11

The course of illness is characterized by the type of episode(s), duration of

euthymic intervals, frequency of relapse, severity of episodes, and predominant

syndrome (mania, hypomania, or depression). These factors do not remain fixed

throughout an individual’s illness. For instance, individuals may experience episodes

of dysphoria and depression before ever experiencing hypomania or mania. Often,

the euthymic interval and cycle length decrease with additional episodes. With time,

a course of alternating recurrent depression interspersed with manic or hypomanic

episodes and no intervening euthymic periods can develop.

A specifier of BD, termed rapid cycling, occurs in both bipolar I and bipolar II

disorder and is defined as a patient experiencing four or more mood episodes per

year. Rapid cycling is common, occurring in 20% of cases; women are more often

affected than men.

13 The rapid cycling type of BD is often refractory to conventional

treatment and carries significant morbidity and mortality because of rapid changes in

mood states.

The prognosis, even for treated BD, is concerning, with 73% experiencing a

recurrent mood episode within 5 years. Furthermore, nearly half of patients continue

to have significant mood symptoms between episodes, whereas less than 20% are

euthymic or have minimal symptoms.

14

Pathophysiology

BD is a complex disease involving developmental, genetic, neurobiologic, and

psychological factors.

15 Neuroimaging studies have demonstrated neurochemical,

anatomic, and functional abnormalities in those with a diagnosis of BD.

16 Recent

studies have demonstrated that altered synaptic and circuit functioning accounts for

mood and cognitive changes rather than the previous theory of dysfunction of

individual neurotransmitters.

17 Environmental, or psychosocial, stressors,

immunologic factors, and sleep dysfunction have been associated with BD and can

negatively influence the course of illness.

18–22

Clinical Presentation

Risk factors for BD include family history of mood disorders, perinatal stress, head

trauma, environmental factors (including circadian rhythm disorders), and

psychosocial and physical stressors. A recent systematic review of 16 published

reports with varying study designs suggested that early phases and suspected

precursor states for those who develop BD include: early-onset panic attacks and

disorder, separation anxiety, generalized anxiety disorders, attention deficient

hyperactivity disorder, and conduct symptoms and disorder.

23

A manic episode usually begins with a change in sleep patterns along with mood

elevation. Presenting symptoms include talkativeness, lack of sleep, and bursts of

energy during which projects are begun but rarely completed. Mania often is

characterized by thought disturbances exhibited by “flight of ideas” (rapid speech

that switches among multiple ideas or topics) and grandiose delusions (false beliefs

of wealth, special powers, knowledge, abilities, importance, or identity). The

behavior of manic patients is characterized as being intrusive, loud, intense, irritable,

at times suspicious, and even challenging. Patients often exercise poor judgment,

which may include spending large sums of money in business deals that ultimately

fail, becoming sexually promiscuous, using substances of abuse, or failing to obey

laws.

The symptoms of mania usually develop gradually over the course of several days

to more than a week and are defined in three stages.

24 Stage I is characterized by

euphoria, irritability, labile affect, grandiosity, overconfidence, racing thoughts,

increased psychomotor activity, and an increase in the rate and amount of speech.

This stage corresponds to an episode of hypomania. Stage II features increased

dysphoria (a feeling of extreme discomfort and unrest), hostility, anger, delusions,

and cognitive disorganization. This stage corresponds to acute mania. Many patients

progress no further than this stage. Others may proceed to stage III, in which the

manic episode progresses to an undifferentiated psychotic state. Individuals in stage

III experience terror and panic, their behavior is bizarre, and psychomotor activity is

frenzied. They may experience hallucinations. What were once simply disorganized

thoughts become incoherent; disorientation to time and place occurs. Just as the

manic episode gradually builds, it often declines in a gradual manner. Psychotic

symptoms usually resolve first, whereas irritability, paranoia, and excessive

behavior persist. Remaining symptoms such as talkativeness, seductiveness, and

dysphoria slowly decrease with time.

Depressive episodes of BD share the diagnostic criteria with unipolar depression;

however, the presentation of bipolar depression has some distinguishing features. In

particular, bipolar depression (type I specifically) is more likely to be associated

with mood lability, psychotic features, psychomotor retardation, and comorbid

substance use.

25 This contrasts with unipolar depression, which is more likely to be

associated with anxiety, agitation, insomnia, somatic complaints, and weight loss.

25

Mixed states appear to be common and could represent a more severe phase of

bipolar illness. These episodes have been associated with a younger age of onset,

more frequent occurrence of psychotic symptoms, major risk for suicide, higher rate

of comorbidities, and longer time to achieve remission.

26–28

A review by Salvatore et al.

29

identified three important presentations of mixed

states: manic stupor, agitated depression, and unproductive mania. Manic stupor, “the

most important of the mixed states,” is characterized by mood elevation with a deficit

in psychomotor

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p. 1836

activity (stupor) and slowed thoughts.

29 Agitated depression occurs when

depressed mood is experienced with psychomotor activation and flight of ideas.

Unproductive mania consists of mood elevation, psychomotor activation, and thought

retardation. Mixed states can occur abruptly or serve as a transitional phase to a

depressed or manic episode. The duration may be short-lived, lasting only days, or

may take on a chronic course of weeks to months.

Patients with BD have higher rates of mortality from both natural and unnatural

causes. Higher rates of natural deaths largely result from cardiovascular disease.

30

Mortality due to cardiovascular disease in BD has been estimated to be twice as

frequent as the general population.

31–33 Rates of cerebrovascular disease, coronary

heart disease/acute myocardial infarction, and cardiac arrest/ventricular fibrillation

are all estimated to be increased in BD patients.

33 Suicide (more likely during

depressive and mixed states) and excessive risk-taking behaviors (more likely to

occur during manic or hypomanic episodes) also contribute to the high mortality rate.

Suicidal behavior is a complex issue that likely depends on both environmental

circumstances and risk factors inherent to BD, and current evidence regarding suicide

risk is likely confounded by multiple risk factors.

34 Lifetime risk for an attempted

suicide is reported to occur in as many as 25% to 50% of patients with BD, while the

lifetime risk of a completed suicide may be as high as 17% to 19%.

35 The most

rigorously determined estimate for completed suicide in BD reports rates of 7.8% in

men and 4.8% in women.

36 Previous suicide attempts and the presence of

hopelessness are primary risk factors for completed suicide.

37 Non-lethal suicidal

behavior also has risk factors that are multifactorial and include a family history of

suicide, younger age at onset, greater severity of mood episodes, the presence of

mixed episode, rapid cycling, comorbid psychiatric conditions, and substance use.

37

Fortunately, overall mortality as well as deaths owing to suicide or cardiovascular

disease are significantly reduced when BD is adequately treated.

14

Approximately 42% of patients with BD have comorbid substance use disorders.

6

The estimated lifetime prevalence of a comorbid substance use disorder in BD

patients is 40% for bipolar I and 20% for bipolar II.

38 Comorbid alcohol use in BD

is estimated at 50%, while comorbid cannabis use is estimated at 30%.

39,40 Those

with rapid cycling and dysphoric mania have the highest rates of substance use.

41 BD

becomes difficult to treat in the face of active substance use. Constant intoxication

and withdrawal not only impact the course of BD but masquerade as mood episodes.

Symptoms are highly recurrent, and treatment resistance is common, as is violence

and suicidal behavior.

42 The best outcome is achieved with aggressive simultaneous

management of both BD and the concurrent substance use disorder.

Individuals with BD are likely to experience stress and upheaval in many areas of

their lives, including relationships, employment, and finances. Of patients with BD,

88% have been hospitalized once and 66% at least 2 times.

43 Divorce rates in those

with BD are two- to threefold higher than those found in non-affected populations.

Patients often report having poor relationships with family members, and nearly 75%

report that their family members have a limited understanding of BD.

9 Employment

problems may result from bizarre, inappropriate, or unreliable behavior. In one

study, 60% of patients reported being unemployed, 88% felt the disease affected how

well they performed at work, and 63% felt that they were treated differently from

their peers.

9 Financial and legal problems are tied to excessive spending,

involvement in schemes, substance abuse, and risk-taking behavior.

Diagnosis

Mood disorders like BD are diagnosed using the criteria established in the

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

12

Discrete periods of mood disturbance associated with BD are defined as manic

episodes, hypomanic episodes, or major depressive episodes with various specifiers

including mixed features and rapid cycling.

Manic or hypomanic episodes (Table 87-1) are periods of abnormally and

persistently elevated, expansive, or irritable mood and persistently increased goaldirected activity or energy.

12 Hypomanic episodes are less intense than manic

episodes, but are severe enough to impair functioning (self-care, occupational,

social), complicate a medical condition, result in psychotic features, or require

hospitalization.

12 Although manic and hypomanic episodes are characteristic

symptoms of BD, it is depressive episodes that predominate and are ordinarily the

initial presenting symptom.

44,45 Major depressive episodes share the same criteria

with major depressive disorder (see Chapter 86, Depression).

12

A person who has experienced one or more manic episodes with or without a

depressive episode is diagnosed as having bipolar I disorder. An individual who has

experienced one or more episodes of both hypomania and depression (without a

history of manic episodes) is diagnosed as having bipolar II disorder.

12

1.

2.

3.

4.

Table 87-1

DSM-5 Criteria for a Manic Episode

A distinct period of abnormally and persistently elevated, expansive, or irritable mood, and persistently

increased goal-directed activity or energy lasting ≥1 week (or of any duration if hospitalization is

necessary).

a

During the period of mood disturbance and increased energy or activity, at least three of the following

symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

Inflated self-esteem or grandiosity

Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)

More talkative than usual or pressure to keep talking

Flight of ideas or subjective experience that thoughts are racing

Distractibility (i.e., attention too easily drawn to unimportant or irrelevant externalstimuli)

Increase in goal-directed activity (either social, at work, at school, or sexually) or psychomotor agitation

Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., the

person engages in unrestrained buying sprees, sexual indiscretions, or foolish business investing)

The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual

social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others,

or there are psychotic features.

The symptoms are not caused by the direct physiologic effects of a substance (e.g., a drug of abuse, a

medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).

aCriteria for a hypomanic episode are identical to a manic episode; however, the symptoms need only be present

for 4 days and are not severe enough to cause marked impairment in social or occupational functioning,

necessitate hospitalization, or for psychotic features to be present.

Manic-like or hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (e.g.,

medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar disorder.

Source: American Psychiatric Association. Mood disorders. In: American Psychiatric Association, ed. Diagnostic

and Statistical Manual of Mental Disorders. 5th ed. Text Revision. Washington, DC: American Psychiatric

Association; 2013;123:124.

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