Medical Pharmacology: Pharmacology of Antidepressant Medications

Antidepressant medications II, continued

Monoamine Oxidase Inhibitors (MAOIs), continued:¹⁰⁷

Selective monoamine oxidase inhibitor antidepressants

Another class of MAO inhibitors is described as "reversible" MAO-A inhibitors or RIMAs.¹⁹²
- The pharmacological rationale for development of MAOIs that bind less strongly to monoamine oxidase is the avoidance of life-threatening hypertensive reactions following ingestion of tyramine-rich foods.¹⁹²
- Irreversible inhibition of MAO, localized in the G.I. tract, prevents local metabolism of tyramine, permitting systemic tyramine access.¹⁹²
  - With a reversible inhibitor (i.e. a more weakly binding inhibitor) as tyramine concentration increases, tyramine gains access to the monoamine oxidase active site and is metabolized.
    - An example of a selective and reversible inhibitor of MAO-A is moclobemide (Manerix, Aurorix); this agent is not available in the United States, not having received FDA approval.
      - Meclobemide (Manerix, Aurorix)
      - It is available in Canada, the United Kingdom and Australia and possibly in other countries as well.
        
        At this point moclobemide is available as a generic drug and it is uncertain if manufacturers will embark on the necessary testing to obtain FDA approval.
- Moclobemide preferentially inhibits MAO-A about 80% and also MAO-B at about 25%.¹⁹²
  - Selectivity is typically concentration-based; therefore, at relatively lower concentrations MAO-A inhibition is favored and as the drug concentration is increased, the selectivity may be reduced.
  - Inhibition of MAO-A and MAO-B results in elevated synaptic and storage site concentrations of serotonin, norepinephrine and other catecholamines.
    - Secondary, CNS adaptive changes, during chronic meclobemide administration, may be responsible for antidepressant activity.
  - Meclobemide plasma concentrations is likely affected by some patients being "poor metabolizers", given that this drug is at least partially metabolized by the cytochrome P450 isoforms, CYP2C19 and CYP2D6. In patients who are poor meclobemide metabolizers, the AUC (area under the curve) is about 1.5 times greater than the AUC in patients receiving the same dose but described as "extensive metabolizers."
Drug interactions for the RIMAs include interaction with serotonin selective reuptake inhibitor-type (SSRIs) antidepressants.¹⁹²

This interaction may result in serotonin syndrome.

Serotonin Syndrome¹⁹⁷

"Serotonergic" medications administration may be associated with a rare but potentially "life-threatening" drug reaction, known as serotonin syndrome or serotonin toxicity.¹⁹⁷
- Drugs typically associated with serotonin syndrome usually are categorized as antidepressants; however, some patients without a history of depression may be prescribed these agents for various other disorders.
- The syndrome is associated with both exposure to a serotonergic drug and some combination of cognitive behavioral change, autonomic nervous system functional change, and altered neuromuscular activity.
  - The extent of abnormality in any one particular area is variable.
  - Activation of a postsynaptic serotonergic receptor subtype, 5-HT_2A , is likely responsible for serotonin syndrome, although other receptor subtypes may be important in explaining the full manifestation of the syndrome.
  - Drugs that inhibit serotonin binding to postsynaptic serotonergic receptors do not induce serotonin syndrome and may be used to treat it.
Most cases of serotonin syndrome develop in patients taking serotonergic drugs at the therapeutic level, although about 10% of cases occur following serotonergic drug overdose.¹⁹⁷
- Serotonin syndrome onset develops relatively soon following administration of the serotonin agonist such as a monoamine oxidase inhibitor (MAOI) or a specific serotonin reuptake inhibitor (SSRI).
Diagnostic challenge:¹⁹⁷
- Nonspecific symptomatology represents a challenge to serotonin syndrome diagnosis.
  - Mild cases might be interpreted incorrectly as associated with other medical or psychiatric disorders.
  - More severe cases may be misdiagnosed as neuroleptic malignant syndrome, associated with administration of antipsychotic agents.
  - A concern in the emergent care setting is that in the absence of considering serotonin syndrome risk, serotonin syndrome may actually be induced by administering a serotonergic drug such as meperidine, dextromethorphan or tramadol.
  - Avoiding this type of event, an iatrogenic cause of serotonin syndrome, requires utilization of drug databases and other resources.
The incidence and severity of serotonin syndrome has been difficult to document with some studies apparently overestimating and others underestimating his frequency and severity.¹⁹⁷
- However, the most commonly found signs and symptoms due to serotonin syndrome are altered mental status, increased muscle tone and hyperthermia.
- The most common finding in serotonin syndrome is myoclonus, which is an important observation, given that myoclonus is not typically seen in other conditions that would otherwise mimic serotonin syndrome.
  - Muscle rigidity is particularly notable in lower extremities and represents another clinical marker for serotonin syndrome.
  - Even patients exhibiting ataxia should be evaluated for hypertonia in lower extremities.
    - However, focal neurologic findings or one-sided muscle rigidity tends not to be consistent with serotonin syndrome.
    - Presentations include seizures (generalized and typically of short-duration), moderately severe hyperthermia (temperatures >106^oF (41^oC) however may occur).
Management of serotonin syndrome begins with discontinuing all serotonergic agents and providing supportive care with about 25% of patients requiring endotracheal intubation and ventilatory support. ^{197,198,199,200,201}
- Dramatic improvement within about a day of symptom onset appears typical; serotonin syndrome mortality is about 11% and the most common cause of death is severe hyperthermia.
- Drugs that may be helpful in management of serotonin syndrome include benzodiazepines, which exhibit nonspecific serotonin antagonism, the administration of which may reduce patient discomfort and facilitate muscle relaxation.
- The most effective anti-serotonergic drug for use in the setting is cyproheptadine.
- Chlorpromazine administration may be helpful, probably due to its blockade of the 5-HT_2A serotonin receptor subtype. By contrast to cyproheptadine, chlorpromazine is available by the IV route of administration; however, chlorpromazine administration may result in undesired hypotension.
- The nonspecific muscle relaxant dantroline has been occasionally used in serotonin syndrome treatment although its use typically is restricted mainly to management of malignant hyperthermia.

Following recovery, the patient should probably avoid subsequent exposure to serotonergic agents even though the risk of recurrence has not been quantified.

Serotonin Syndrome and Neuroleptic Malignant Syndrome: Presentation by Dr. Ahmed Mian¹⁹⁶

Attribution: Mian A Serotonin Syndrome and Neuroleptic Malignant Syndrome https://www.youtube.com/watch?v=TKdUqWGAgTU Emergency Medicine London YouTube Channel: https://www.youtube.com/channel/UCwtOe9nC7DbSjzb691pOoZQ

Pharmacological affects of some stimulant drugs, including methylphenidate and dextromethamphetamine, which are used in ADHD management, may be increased.
A selective MAO-B inhibitor, selegiline, which may be used in management of Parkinson's disease should not be given along with RIMAs.

Concerning hypertensive crisis: one of the life-threatening toxicities associated with MAOIs, as noted earlier, is an elevation in blood pressure following ingestion of foods containing tyramine.¹⁰⁷
- The degradation of dietary tyramine occurs due to actions of MAO-A within the intestinal wall and MAO-A and MAO-B within the liver. Inhibition of MAO-A and ingestion of certain foods rich in tyramine, including red wines, sauerkraut, fava beans, certain aged cheeses and other foods lead to tyramine accumulation at adrenergic nerve endings and within neurotransmitter vesicles; furthermore, tyramine accumulation induces norepinephrine and epinephrine presynaptic release.¹⁰⁷
- Activation of peripheral postsynaptic receptors induces substantial blood pressure elevation. ¹⁰⁷
  - This effect is likely mediated by activation of α-type vascular adrenergic receptors.
  - Compared to tranylcypromine and isocarboxazid, selegiline delivered transdermally appears both better tolerated and safer.
  - Another concern is that chronic MAOI administration may be associated with hepatotoxicity.
MAO-A inhibitors appear effective in managing depression; moreover, MAO-B inhibitors including oral formulations of selegiline are also effective in treating depression if the dose is sufficient to block both MAO-A and MAO-B enzyme forms.¹⁰⁷
- Selegiline is also available as a drug patch.
- Other drug-drug interactions involving MAO inhibitors:¹⁰⁷
  - A variety of drugs are contraindicated for concurrent use with monoamine oxidase inhibitors (MAOIs).
    - These include CNS depressants, as well as meperidine (Demerol) and other opioids.
      - Opioid agonists such as meperidine when administered in the presence of monoamine oxidase inhibitors may precipitate serotonin syndrome.
      - Antidepressant medications belonging to SSRI and SNRI categories should not be administered in patients taking MAOIs.
        
        Such combinations may also predispose to serotonin syndrome.
  - Tricyclic antidepressants (TCAs) and bupropion should also not be administered to patients receiving MAOIs.
  - Anesthetic agents should also not be administered with MAOIs.

References
Reus VI Mental Disorders, Chapter 386 in Harrison's Principles of Internal Medicine, 17th edition (Fauci AS Braunwald E Kasper DL Hauser SL Longo DL Jameson JL Loscalzo J, Eds.), McGraw-Hill, New York, on-line edition, 2008. Loosen PT Shelton RC Mood Disorders, Chapter 18 in Current Diagnosis and Treatment: Psychiatry, 2nd edition (Ebert MH Loosen PT Nurcombe B Leckman JF, Eds), McGraw-Hill, New York, on-line edition, 2008. CC-BY-SA-2.1-jp (Polygon data are from BodyParts 3D) Author: Polygon data generated by Life Sciences Databases (LSDB). Rotating animation of the human brain. http://en.wikipedia.org/wiki/File:Frontal_lobe_animation.gif . Mysid, Principal fissures and lobes of the cerebrum (lateral view) Figure 728 from Gray's Anatomy. http://en.wikipedia.org/wiki/File:Lobes_of_the_brain_NL.svg . Badre D Cognitive control, hierachy, and the rostro-caudal organization of the frontal lobes Trends in Cognitive Sciences, vol 12, issue 5, 193-200, May 2008. Pasquini M Biondi M Depression in cancer patients: a critical review Clinical Practice and Epidemiology in Mental Health 3:2 2007, on-line edition, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797173/ . Grassi L, Rosti G: Psychiatric and psychosocial concomitants of abnormal illness behaviour in patients with cancer. Psychother Psychosom 1999, 65:246-252. Sharpe M Strong V Allen K Rush R Postma K Tulloh A Maguire P House A Ramirez A Cull A: Major depression in outpatients attending a regional cancer centre: screening and unmet treatment needs. Br J Cancer 2004, 90(2):314-20. Prieto JM Atala J Blanch J Carreras E Rovira M Cirera E Espinal A Gasto C: Role of Depression as a predictor of mortality among cancer patients after stem-cell transplantation. J ClinOncol 2005, 23:6063-6071. Coyne JC Palmer SC Shapiro PJ Thompson R DeMichele A: Distress, psychiatric morbidity, and prescriptions for psychotropic medication in breast cancer waiting room sample.Gen Hosp Psychiatry 2004, 26:121-128. Ell K, Sanchez K Vourlekis B Lee PJ Dwight-Johnson M LagomasinoI, Muderspach L, Russell C: Depression, correlates of depression, and receipt of depression care among low-income women with breast or gynecologic cancer. J Clin Oncol 2005,23:3052-3060. Okamura M Yamawaki S Akechi T Taniguchi K Uchitomi Y: Psychiatric disorders following breast cancer recurrence: prevalence, associated factors and relationship to quality of life. Jpn J Clin Oncol 2002, 35(6):302-309. Burgess C Cornelius V Love S Graham J Richards M Ramirez A: Depression and anxiety in women with early breast cancer: five year observational cohort study. BMJ 2005, 330:702-707. Fasciano K and Miller K Depression and anxiety after cancer treatment: Conversations on Survivorship, Lance Armstrong Foundation Adult Survivorship Program; Perini Family Survivors' Center: Dana-Farber Cancer Institute. http://www.youtube.com/watch?v=J1WjHi3IXSA . Servaes P Verhagen C Bleijenberg G. Fatigue in cancer patients and after treatment: Prevalence, correlates and interventions. Eur J Cancer 38: 27-43, 2002. Morrow GR Hickok JT Roscoe JA Raubertas RF Andres PL Flynn PJ Hynes HE Banerjee TK Kirshner JJ King DK Differential effects of paroxetine on fatigue and depression: a randomized , double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program J Clin Oncol 21: 4635-4641, 2003. Capaldini L Feldman HIV/AIDS: Chapter 33 in Behavioral Medicine: A Guide for Clinical Practice 3rd edition (Feldman MD Christensen JF, eds). on-line edition, 2008. HIV Lifecycle- "GlaxoSmithKline commissioned a three minute film on the life of cycle of the HIV virus,with an emphasis on the mechanism of the integrase molecule in its role in inserting the AIDS virus genome into the host T-cell DNA." (2002) http://www.youtube.com/watch?v=9leO28ydyfU . The Diagnostic and Statistical Manual of Mental Disorders, 4th edn., Text Revision. Washington DC: American Psychiatric Association, 2000. Josephson SA Method of attempted suicide predicts risk for future completed suicide, 8/12/2010 in: eus VI Mental Disorders, Chapter 386 in Harrison's Principles of Internal Medicine, 17th edition (Fauci AS Braunwald E Kasper DL Hauser SL Longo DL Jameson JL Loscalzo J, Eds.), McGraw-Hill, New York, on-line edition, 2008. Runeson B Tidemalm D Dahlin M Lichtenstein P Langsgtrom N Method of attempted suicide as predictor of subsequent successful suicide: national long term cohort study. BMJ 340: c3222, 2010 (10 July 2010). Barrett JE Barrett JA Oxman TE Gerber PD The prevalence of psychiatric disorders in a primary care practice Arch Gen Psychiatry 45: 1100-1106, 1988. Bourdon KH Rae DS Locke BZ Narrow WE Regier DA Estimating the prevalence of mental disorders in U.S. adults from the Epidemiologic Catchment Area Survey. Public Health Rep. 107(6): 663-668, 1992. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1403718/ . Wishnie HA Hackett TP Cassem NK Psychological hazards of convalescence following myocardial infarction. JAMA 215(8): 1292-1296, Feb 22, 1971. Wynn A Unwarrented emotional distress in men with ischaemic heart disease (IHD). Med. J. Aust 2: 847-851, 1967. Ropper AH Samuels MA Chapter 57: Depression and Bipolar Disease in Adams & Victor's Principles of Neurology, 9th edition, 2009, online edition. Starkstein SE Robinon RG Price TR Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 110(4) 1045-1059, 1987. Robinson RG Poststroke mood disorder. Hosp. Pract. 83-89, 1986. Carson AJ, MacHale S, Kathryn A Lawrie ASM Dennis M House A Sharpe M Depression after stroke and lesion location: a systematic review. The Lancet 356 (9224), 122-126, 8 July 2000. Bhogal SK Teasell R Foley N Speechley M Lesion location and poststroke depression. Systematic review of the methodological limitations in the literature. Stroke 35: 794-802, 2004. Cadoret RJ Winokur G Depression in alcoholism. Ann N Y Acad Sci 233: 34-39, 1974. Kessler RC Crum RM Warner LA Nelson CB Schulenberg J Anthony JC Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Study. Arch Gen Psychiatry, 54: 313-321, 1997. Conner KR Pinquart M Gamble SA Meta-analysis of depression and substance use among individuals with alcohol use disorders. Journal of Substance Abuse Treatment 37: 127-137, 2009. Cohen J A power primer. Psychological Bulletin 112: 155-159, 1992. Rosenthal R Meta-analytic procedures for social research. Beverly Hills, CA: Sage 1991. Chronis-Tuscano A Molina BSG Pelham WE Applegate B Dahlke A Overmeyer M Lahey BB Very early predictors of adolescent depression and suicide attempts in children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 67 (10): 1044-1051, 2010. Messing RO Rubensterin JH Nestler EJ Chapter 390 Biology of Psychiatric Disorders Harrison's Online 18th edition (Longo, DL Kasper DL Jameson JL Fauci AS Hauser SL Loscalzo J, eds) The McGraw-Hill Companies, Inc, 2012. Pleotrope, Structure of protein CRHR1 (Based on PyMOL rendering of PDB (protein data base) 3EHS: 8/3/2011. http://en.wikipedia.org/wiki/File:Protein_CRHR1_PDB_3EHS.png Corticotropin releasing hormone receptor 1 (http://en.wikipedia.org/wiki/Corticotropin_releasing_hormone_receptor_1). Ising M Holsboef F CRH1 receptor antagonists for the treatment of depression and anxiety. Exp Clin Psychopharmacol 15(6): 519-528, 2007. Boghob2/Gonn Glucocorticoid Receptor, created using PyMol and ChemDraw, 7/22-23, 2007 .http://en.wikipedia.org/wiki/File:Glucocorticoid_receptor.png. Swaminathan J, MSD staff at the European Bioinformatics Institute, TIF2 coactivator protein (transcriptional mediators/intermediary factor 2), a.k.a glucocorticoid receptor interacting protein 1 (GRIP2), steroid receptor coactivator-2 (SRC-2). http://en.wikipedia.org/wiki/File:PDB_1gwq_EBI.jpg . Hong H Kohil K Garabedian MJ Stallcup MR GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid,, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 17(5): 2735-2744 1997. Binder EB Salykina D Lichtner P et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genetics, 16(12) 1319-1325, December, 2004. Csermely P Schaider T Soti C Prohaszka Z Nardai G The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol. Ther. 79(2): 129-168, 1998. Emw, Structure of the PKBP5 protein using a PyMOL rendinger of PDB 1kt0. http://en.wikipedia.org/wiki/File:Protein_FKBP5_PDB_1kt0.png . Tirkfl Hsp90 cycle http://en.wikipedia.org/wiki/File:Hsp90cycle.jpg . Hsp90 http://en.wikipedia.org/wiki/Hsp90 . Goodwin DW Guze SB Psychiatric Diagnosis, 5th ed, New York, Oxford University Press, 1996. Levinson DF The Genetics of Depression: A Review, Biol. Psychiatry 60: 84-92, 2006. Maier W Lichtermann D Minges J Heun R Hallmayer J Benkert O Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: Keep separate or combine? Evidence from a family study. Am J Psychiatry 149: 1666-1673. Kendler KS Kuhn JW Prescott CA Childhood sexual abuse, stressful life events and risk for major depression in women. Pychol Med 34: 1475-1482. DeNeve KM Cooper H. The happy personality: A meta-analysis of 137 personality traits and subjective well-being. Psychol Bull 124: 197-229, 1998. Jang KL Livesley Wj Vernon PA Heritability of the big five personality dimensions and their facits: a twin study. J Pers 64: 577-591, 1996. Kendler KS Neale MC Kessler RC Heath AC Eaves LJ A longitudinal twin study of personality and major depression in women. Ach Gen Psychiatry 50: 863-862, 1993. Granet D Stein M "What is Social Anxiety Disorder", University of California, San Diego: Health Matters Series, http://www.youtube.com/watch?v=4truuD_xMP0 . Pine D. National Institutes of Health, Genes and treatment for depression and anxiety. http://www.youtube.com/watch?v=mzNdE6kD5tc . Risch N Herrell R Lehner T Liang K-Y Eaves L Hoh J Griem A Kovacs M Ott J Merikangas KR Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. JAMA 301(23) 2462-2471 (2009). Walther DJ Bader M A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. 66: 1673-1680. Zill P Baghal TC Zwanzger P Schule C Eser D Rupprecht R Moller H-J Bondy B Ackenheil SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Molecular Psychiatry 9, 1030-1036, 1004. Pereira PA Romano-Silva A Bicalho MAC De Marco L Correa H de Campos SB de Moraes EN de Lima Terres KC de Souze BR de Miranda DM Association between tryptophan hydroxylase-2 gene and late-onset depression. Am J Geriatr Psychiatry 19(9) 825-829, 2011. Van Dan Bogaert A Sleegers K De Zutter S Heyrman L Norrback K-F Adolfsson R Van Broeckhoven C Del-Favero J Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a northern Swedish, isolated population. Arch Gen Psychiatry 63(10) 1103-1110, 2006. Tsai SJ Hong CJ Liou YJ Yu YW Chen TJ Hou SJ Yen FC Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response. Prog Neuropsychopharmacol Biol Psychiatry 33(4): 637-641, 2009. CNSforum image bank, Lundbeck Institute "Mechanism of action of 5-HT re-uptake transporters" http://www.cnsforum.com/imagebank/item/Rcpt_sys_SN_transp/default.aspx . Windahl MS Serotonin biosynthesis pathway, http://proteopedia.org/wiki/index.php/Image:Indoleamin_chain.png . Windahl MS Canner D Harel M Berchansky Tryptophan hydroxylase http://proteopedia.org/wiki/index.php/Tryptophan_hydroxylase . Kanellopoulos D Gunning FM Morimoto SS Hoptman MJ Murphy CF Kelly, Jr RE Glatt C Lim KO Alexopoulos GS Hippocampal volumes and the brain-derived neurotrophic factor val66met polymorphism in geriatric major depression. Am J Geriatr Psychiatry 19(1): 13-22, January 2011. Ballmaier M Narr KL Toga AW Elderkin-Thompson V Thompson PM Hamilton L Haroon E Pham D Heinz A Kuman A Hippocampal morphology and distinguishing late-onset from early-onset elderly depression Am J Psychiatry 165: 229-237, 2008. Ashtari M Greenwald BS Kramer-Ginsberg E Hu J Wu H Patel M Aupperle P Pollack S Hippocampal/amygdala volumes in geriatric depression Psychol med 29: 629-638, 1999. Bueller JA Aftab M Sen S Gomez-Hassan D Burmeister M Zubieta J-K BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59: 812-815, 2006. Bath KG Lee FS Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 6: 79-85, 2006. BDNF Pathway Qiagen Sample & Assay Technology https://www.qiagen.com/geneglobe/pathwayview.aspx?pathwayID=55 . Microswitch BDNF structure, Protein Data Bank http://en.wikipedia.org/wiki/File:1BND.png . Brain-derived neurotrophic factor, http://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor . Devets WC Neuroimaging and neuropathological studies of depression: Implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 11(2): 240-249, Apr 2001. Herzog J Reiff J Krack P Wit K Schrader B Muller D Deuschl G Manic episode with psychotic symptoms induced by subthalamic nucleus stimulation in a patient with Parkinson's disease. Mov Disord 18(11) 1382-1384, 2003. Sapolsky RM Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders Arch Gen Psychiatry 57(10): 925-935, Oct. 2000. CNSforum image bank, Lundbeck Institute "The areas of the brain affected in depression. http://www.cnsforum.com/imagebank/item/brain_struc_DPN/default.aspx . Zellner M Neuroanatomy and pharmacology of depression http://www.veoh.com/watch/v7081348RpNXAY3q?searchId=810970478899992789&rank=11 . Lee S Jeong J Kwak Y Park SK Depression research: where are we now? Molecular brain 3: 8 2010 http://www.molecularbrain.com/content/3/1/8 . Kramer MS Cutler N Feighner J Shrivastava R Carman J Sramek JJ Reines SA Liu G Snavely D Wyatt-Knowles E Hale JJ Mills SG MacCoss M Swain CJ Harrison T Hill RG Hefti F Scolnick EM Casieri MA Chicchi GG Sadowski S Williams AR Hewson L Smith D Carlson EJ Hargreaves RJ Rupniak NM Distinct mechanism for antidepressant activity by blockade of central substance P receptors Science 281(5383) 1640-1645, 11 September 1998. Schlesser MA Winokur G Sherman BM Hypothalamic-pituitary-adrenal axis activity in depressive illness. Arch Gen Psychiatry 37(7): 37-743 1980. Dopamine and Serotonin pathways, http://en.wikipedia.org/wiki/File:Dopamineseratonin.png . The dopamine pathways in the brain, Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/Neuro_path_DA/default.aspx . CNSforum image bank, Lundbeck Institute The hpothalamic-pituitary-adrenal (HPA) axis Lundbeck Institute CNSforum http://www.cnsforum.com/imagebank/item/HPA_NORM_DPN_3/default.aspx . Pleotrope Structure of protein CRHR1, based on PyMol rendering of PDB (Protein Data Base) model. http://en.wikipedia.org/wiki/File:Protein_CRHR1_PDB_3EHS.png . Zoumakis E Rice KC Gold PW Chrousos GP Potential uses of corticotropin-releasing homone antagonists. Ann. New York Acad Sci 1083: 239-251 2006. Pfennig A Frye MA Koberle U Bauer M The mood spectrum and hypothalamic-pituitary-thyroid axis Psychiatry Weekly http://www.psychweekly.com/aspx/article/articledetail.aspx?articleid=48 . Haggstrom M Overview of thyroid system http://en.wikipedia.org/wiki/File:Thyroid_system.png . Johnson AF, Psychoanalysis: An Introduction (support from the North Carolina Psychoanalytic Foundation) http://www.youtube.com/watch?v=WiLtQATY_1s . Beck J Cognitive Therapy http://www.youtube.com/watch?v=45U1F7cDH5k . Leahy RL What is Cognitive Therapy Part 1 http://www.youtube.com/watch?v=gdFovvVJpr8 . see www.cognitivetherapynyc.com . Leahy RL What is Cognitive Therapy Part 2 http://www.youtube.com/watch?v=a4o2ujvXsmM .see www.cognitivetherapynyc.com . Beck AT Cognitive Therapy. A 30 year retrospective. Am Psychol 46: 358-375 1991. Rupke SJ Blecke D Renfrow M Congitive Therapy for Depression American Family Physician 73(1) 83-86, 2006. http://www.aafp.org/afp/2006/0101/p83.html . Rush AJ Beck AT Kovacs M Hollon S Comparative efficacy of cognitive therapy and pharmacotherapy in the treatment of depressed outpatients Cognitive Therapy Research 1: 17-37, 1977. Dobson KS A meta-analysis of the efficacy of cognitive therapy for depression. J Consult Clin Psychol 57: 414-419, 1989. Robinson LA Berman JS Neimeyer RA Psychotherapy for the treatment of depression. Psychol Bull 108: 30-49, 1990. Glaguen V Cottraus J Cucherat M Blackburn IM A meta-analysis of the effects of cognitive therapy in depression patients J Affect Disord 49: 59-72, 1998. DeRubeis RJ Gelfand LA Tang TZ Simons AD Medications versus cognitive behavior therapy for severely depressed outpatients; meta-analysis for four randomized comparisons Am J Psychiatry 156: 1007-1013, 1999. Wampold BE Minami T Baskin TW Callen-Tierney S A meta-(re) analysis of the effects of cognitive therapy versus 'other therapies' for depression. J ffect Disord 68: 159-165 2002. Elkin I Shea MT Watkins JT Imber SD Sotsky SM Collins JF Glass DR Pikonis PA Leber WR Docherty JP Fiester SJ Parloff MB National Institute of Mental Health Treatment of Depression Collaborative Research Program: general effectiveness of treatments General effectiveness of treatments Arch Gen Psychiatry 46: 971-982, 1989. Murphy G Simons AD Wetzel RD Lustman PJ Cognitive therapy and pharmacotherapy Arch Gen Psyciatry 441: 33-41 1984. Hollon SD DeRubeis RJ Evans MD Wiemer MJ Garvery MJ Grove WM Tuason VB Cognitive therapy and pharmacotherapy for depression: singly and in combination. Arch Gen Psychiatry 49: 774-781 (1992). Cole SA Christensen JF Cole MR Cohen H Feldman MD Chapter 22. Depression in Behavioral Medicine: A Guide for Clinical Practice, (Feldman MD and Christensen JF, eds) 3rd edition, 2008, on-line edition. Jamison KR Personal Reflections on Manic-Depressive Illness http://www.youtube.com/watch?v=CxRLap9xLag . O'Donnell JM and Shelton RC Drug therapy of depression and anxiety disorders in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12the edition (Brunton LL, editor, Chabner BA, Knollmann BC, associate eds), Chapter 15, 397-415. 2011. Millan MG Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Thery, 110: 135-170. Rush AJ Trivedi MH Wisniewski SR Nirenberg AA Steward JW Warder D Niederhe G Thase ME Lavori PW Lebowitz McGrath PJ Rosenbaum JF Sackeim HA Kupfer DJ Luther J Fava M Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STARD report Am J Psychiatry 163: 1905-1917, 2006. Delgado PL Miller HL Salomon RM Licinio J Krystal JH Moreno FA Heninger GR Charney DS Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin the mechanism of antidepressant action. Biol Psychiatry 46: 22-220 1999. Catecholamine Biosynthesis: The Interactive Library; Edinformatics.com: http://www.edinformatics.com/interactive_molecules/info/adrenaline.htm . NEUROtiker Biosynthesis of serotonin (5-hydroxytryptamine, 5-HT) http://en.wikipedia.org/wiki/File:Serotonin_biosynthesis.svg . CNSforum image bank, Lundbeck Institute "The normal process of 5-HT and noradrenaline neurotransmission" http://www.cnsforum.com/imagebank/item/Drug_SNRI_norm/default.aspx . CNSforum image bank, Lundbeck Institute "The mechanism of action of specific 5-HT re-uptake inhibitors" http://www.cnsforum.com/imagebank/item/Drug_SSRI_2/default.aspx . CNSforum image bank, Lundbeck Institute "The mechanism of action of specific noradrenaline re-uptake inhibitors" http://www.cnsforum.com/imagebank/item/Drug_NARI_2/default.aspx. Delgado PL Price LH Heninger GR Charney DS Neurochemistry of affective disorders. In: Paykel ES, ed. Handbook of Affective Disorders, 2nd ed. London: Chruchill Livingstone, 1992. Shopsin B Friedman E Gershon S Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients Arch Gen Psychiatry 33: 811-819, 1976 (second sourced from reference 116). Shopsin B Gershon S Goldstein M Friedman E Wilk S Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients Psychopharmacol Comm 1: 239-249, 1975 (second sourced from reference 116). Delgado PL Price LH Miller HL Salomon RM Licinio J Krystal JH Heninger GR Charney DS Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 27(3): 321-330, 1991. Miller HL Delgado PL Salomon RM Heninger GR Charney DS Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients Neuropsychopharmacology 14: 151-157, 1996 (second sourced from reference 107). Schmidt HD Duman RS The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behavioural Pharmacology, 18: 391-488, 2007. Droual R Brain Stem Model: Corpus Callosum & Hippocampus http://www.youtube.com/watch?v=YJLHDPTrUYk . Life Science Databases (LSDB) http://en.wikipedia.org/wiki/File:Hippocampus.gif . Zhao A Baros AM Zhang H-T Lapiz MDS Bondi CO Morilak DA O'Donnell JM Norepinephrine transporter regulation medicates the long-term behavioral effects of the antidepressant desipramine. Neuropsychopharmacology 33, 3190-3200 (2008). Andersen J Kristensen AS Bang-Andersen B Stromgaard K Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters Chem. Commun, 3677-3692, 2009. Mdac927 "Simplified structure of the norephinephrine transporter protein. The protein is 617 amino acids long and consists of 12 transmembrane domains." http://en.wikipedia.org/wiki/File:NET_structure_picture.png . Ordway GA Stockmeier CA Cason GW Klimek V Pharmacology and distribution of norepinephrine transporters in the human locus coeruleus and raphe nuclei. The Journal of Neuroscience, 17(5): 1710-1719, 1997. CNSforum image bank, Lundbeck Institute "Areas of the brain affected in phobia" (Am. J. Psychiatry, 157; 157: 493-505, 2000.) http://www.cnsforum.com/imagebank/item/Neuro_biol_PHB/default.aspx . CNSforum image bank, Lundbeck Institute "The noradrenaline pathways in the brain" http://www.cnsforum.com/imagebank/item/Neuro_path_N/default.aspx . Schou M Halldin C Pike VW Mozley PD Dobson D Innis RB Farde L Hall H Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[¹⁸F]FMeNER-D₂. European Neuropsychopharmacology 15, 517-520, 2005. Baudry A Mouillet-Richard S Schneider B Launay J-M Kellermann O MiR-16 targets the serotonin transporter: a new fact for adaptive responses to antidepressants. Science 229: 1537-1541, 17 September 2010. [131b: supporting on-line material for reference 131, http://www.sciencemag.org/content/suppl/2010/09/15/329.5998.1537.DC1 ] Esposito G De Filippis D Cirillo C Samelli G Cuomo R Iuvone T The astroglial-derived S100β protein stimulates expression of nitric oxide synthase in rodent macrophages through p38 MAP kinase activation. Life Sciences 78(23) 2707-2715, 2006. MoodyGroove Sinus Tachycardia http://en.wikipedia.org/wiki/File:SinusTach.jpg . RichACLS ECG rhythm review: sinus rhythm, sinus bradycardia, sinus tachycardia, http://www.youtube.com/watch?v=mA3GuXQ6UTM . http://www.richacls.com/ . HeartStartSkills Atrial Tachycardia http://www.youtube.com/watch?v=9RNhr36KlW0 . The physiology of cardiac output http://www.youtube.com/watch?v=0v8-O8P7kw8 . http://www.virtualmedstudent.com/ . Illumistream health (Healthguru) http://www.youtube.com/watch?v=ngi4Hyzp11k . Jefferson JW A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychomatic Medicine 37(2) March-April, 160-179, 1975. Moorehead CN Knox SJ Imipramine induced auricular fibrilation. Am J Psychiat 122: 216-217, 1965. Smith RB Rusbatch BJ Amitriptyline and heart block. Br Med J 3: 311, 1972. Rasmussen EB Kristjansen P ECG changes during amitriptyline treatment. Am J Psychiat 119: 781-782, 1963. Gilman R ECG Rhythm Review: AV Blocks http://www.youtube.com/watch?v=-uxfPhiCYSA . http://www.richacls.com/ . Monomorphic Ventricular Tachycardia (simulated by a TechPatient CARDIO ECG Simulator with the Ritmic Module Arrhythmia Simulator installed) http://www.youtube.com/watch?v=idlUHTVzOkw ; http://www.heinstruments.com/arrhythmia-simulator.htm . Ferguson JA SSRI antidepressant medications: Adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 3(1) 22-27, February 2001. Guzman F SSRI side effects: Pharmacology Corner, http://www.youtube.com/watch?v=at-B4UuMrW0 . Cascade E Kalali AH Kenned SH Real-world data on SSRI antidepressant side effects, Innovations in Clinical Neuroscience, February 2009, http://www.innovationscns.com/real-world-data-on-ssri-antidepressant-side-effects/ . Thase ME Haight BR Richard N Rockett CB Milton M Modell JB VanMeter S Harriett AE Wang Y Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized trials. J Clin Psychiatry 66(6) 974-981, 2006. Clayton AH Croft HA Horrigan JP Wightman DS Krishen A Richard NE Modell JB Bupropion extended release compared with escitalopram: effects on sexual functionning and antidepressant activity efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 65(5) 736-746, 2006. Clayton AH Antidepressant-associated sexual dysfunction: A potentially avoidable therapeutic challenge. Primary Psychiatry 10(1), 55-61, 2003. Kanaly KA Berman JR Sexual side effects of SSRI medications: potential treament strategies for SSRI-induced female sexual dysfunction. Curr Women's Health Rep 2(6) 409-416, 2002. Anderson JW Greenway FL Fujoka K Gaddle KM McKenney J O'Neil PM Bupropion SR enhances weight loss: a 48-week double-blind placebo-controlled trial. Obesity Research 10, 633-641, 2002. Baldwin DS Papakostas GI Symptoms of fatigue and sleepiness in major depressive disorder. J Clin Psychiatry 67 (suppl 6) 9-15, 2006. Reuters: The doctor's channel. "Bupropion aids smoking cessation in patients with schizophrenia http://www.youtube.com/watch?v=gLRvYOiZcBc . FDA patient safety news: Warning on neuropsychiatric effects from smoking cessation drugs (Sept. 2009). http://www.youtube.com/watch?v=OGP93A-03xM . user "Nephron" Gynecomastoid hyperplasia. http://en.wikipedia.org/wiki/File:Gynecomastoid_hyperplasia_-_intermed_mag.jpg . Copeland DA Blau M Patient with asymmetric gynecomastia http://en.wikipedia.org/wiki/File:Asymmetric_Gynecomastia.jpg . http://www.gynecomastia-md.com/ . Hunt-Fugate AK Zander J Lesar TS Adverse reactions due to dopamine blockade by amoxapine; a case report and review of the literature. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 4(1) 35-39, January-February 1984; published on-line 24 Jan 2012, http://onlinelibrary.wiley.com/doi/10.1002/j.1875-9114.1984.tb03310.x/abstract . Dystonia fact sheet. National Institute of Neurological Disorder and Stroke http://www.ninds.nih.gov/disorders/dystonias/detail_dystonias.htm ; http://en.wikipedia.org/wiki/Dystonia . Heilman J A person with medication induced dystonia (This person has given both both verbal and written consent for its use on Wikipedia and release into the CC). http://en.wikipedia.org/wiki/File:Dystonia2010.JPG . For use on this website part of the image has been blackened out. Psychiatryteacher Acute Dystonia: http://www.youtube.com/watch?v=Gjiy1rDZpp8 .\ RDDA86, Youtube contributor, Recognizing extrapyramidal symptoms, Part 1 http://www.youtube.com/watch?v=WAg2iLEWVh0 . RDDA86, Youtube contributor, Recognizing extrapyramidal symptoms, Part 2 http://www.youtube.com/watch?v=QYYx1mZDpPw . Phronitis, Akathisia, "Akathisia": "Typical symptoms like motor restlessness of a patient suffering from akathisia (note that she's forced to eat while standing instead of sitting)." http://en.wikipedia.org/wiki/File:Akathisie.ogg . Asayeh K Combination of trazodone and phenothiazines: a possible additive hypotensive effect. Canadian Journal of Pyschiatry 31(9) 857-858, 1986. Bashore TM Granger CG Hranitzky P Patel MR Heart Disease (Chapter 10) in Current Medical Diagnosis & Treatment 2012 (McPhee SJ Papadakis MA, eds; Rabow, MW, assoc. ed), 51st edition, The McGraw-Hill Companies, 2012, on-line edition. Hollister LE Current antidepressant drugs: Their clinical use. Drugs, 22: 129-152, 1981. Son S-Y Ma J Kondou Y Yoshimura M Yamashita E Tsukihara T Structure of human monoamine oxidase A at 2.2 A^o resolution: the control of opening the entry for substrates/inhibitors. PNAS 105(15) 5739-5744 April 15, 2008. De Colibus L Li M Binda C Lustig A Edmondson DE Attevi A Three-dimensional structure of human monoamine oxidase A (MAO A): relation the the structures of rat MAO A and human MAO b PNAS 102(36) 12684-12689, September 6, 2005. Caspi A McClay J Moffitt TE Mill J Martin J Craig IW Taylor A Poulton R Role of genotype in the cycle of violence in maltreated children. Science 297, 851-853, 2002. Arai R Karasawa N Kurakawa K Kanai H Horiike K Ito A Differential subcellular location of mitochondria in rat serotonergic neurons depends on the presence and the absence of monoamine oxidase type B. Neuroscience 114(4) 825-835, 2002. "Gabethenerd" General reactionof the oxidative deamination of an amine catalyzed by a monoamine oxidase. http://en.wikipedia.org/wiki/File:General_reaction_of_the_oxidative_deamination_of_an_amine,_catalyzed_by_a_monoamine_oxidase.jpg . Fvasconcellos Ribbon diagram of a monomer of human monoamine oxidase A, with FAD and clorgiline bound, oriented as if attached to the outer membrane of a mitochondrion.http://en.wikipedia.org/wiki/File:Monoamine_oxidase_A_2BXS.png . Retama Redox equilibrium between FAD and FADH₂ . http://en.wikipedia.org/wiki/File:FAD_FADH2_equlibrium.png . Edgar181 Chemical structure of flavin adenine dinucleotide (ChemDraw). http://en.wikipedia.org/wiki/File:Flavin_adenine_dinucleotide.png . Williams DA Antidepressants (Chapter 21) in Foye's Principles of Medicinal Chemistry, Sixth Edition (Lemke TL, Williams DA, eds; Roche VF, Zito SW, asst. eds) Wolters Kluwer/Lippincott Williams & Wilkins, 547-600, 2008. Chen JJ Swope DM and Dashtiour K Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. Clinical Therapeutics, 29(9), 1825-1849, 2007. Riederer P and Youdim MB, Monoamine oxidase activity and monoamine metabolism in brains ofparkinsonian patients treated with I-deprenyl, J Neurochem* 46 (1986), pp. 1359–1365. Youdim MB and Finberg JP, Monoamine oxidase In:. In: A Lajtha, Editor, Handbook of Neurochemistry, Enzymes in the Nervous System 4, Plenum Press, New York, NY (1983), pp. 293–313. Saura Marti J Kettler R, Da Prada M and Richards JG, Molecular neuroanatomy of MAO-A and MAO-B, J Neural Transm Suppl. 32 (1990), pp. 49–53. Binda C, Hubálek F, Li M, et al. (2005). "Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis". Journal of medicinal chemistry 48 (26): 8148–54. Chen JJ and Swope DM Clinical pharmacology of rasagiline: A novel, second-generation propargyline for the treatment of Parkinson Disease, J Clin Pharmacol 2005 45: 878-894, on-line version. Ropper A.H., Samuels M.A. (2009). Chapter 38. Developmental Diseases of the Nervous System. In A.H. Ropper, M.A. Samuels (Eds), Adams and Victor's Principles of Neurology, 9e. on-line version. Shih JC Chen K Ridd MJ Monamine Oxidase: From Genes to Behavior Annu. Rev. Neurosci. 22: 197-217, 1999. Johnston JP Some observations upon a new inhibitor of monoamine oxidase in brain tissure. Biochem. Pharmacol. 17(7), 1285-1297, 1968. Bach AW Lan NC Johnson DL Abell CW Bembenek ME Kwan SW Seeburg PH Shih JC cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc. Natl. Acad. Sci. USA, 85: 4934-38, 1988. Norrie disease: summary pamphlet from the Norrie disease association and Massachusetts General Hospital and Harvard Medical School. http://www.medmolgen.uzh.ch/services/download/Flyer_ND.pdf X-linked recessive, handbook illustration, Genetics Home Reference, NIH: http://ghr.nlm.nih.gov/handbook/illustrations/xlinkrecessivemother . Bhola R (contributor): Category: pediatrics; Diagnosis: Tractional Retinal Detachment in Norrie's Disease. EyeRounds Online Atlas of Opthalmology. University of Iowa Healthcare Opthalmology and Visual Sciences: http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Tractional-Retinal-Detachment-in-Norries-disease.html . Willoughby J Glover V Sandler M Histochemics localization of monoamine oxdiase A and B in rat brain. J. Neural Transm. 74(1): 29-42, 1988. Saura J Richards JG Mahy N Age-related changes in MAO in Bl/C57 mouse tissues: a quantitative radioautographic study. J. Neural Transm 41: 89-94, 1994. Jahng JW Houpt TA Wessel TC Chen K Shih JC Joh TH Localization of monoamine oxidase A and B mRNA in the rat brain by in situ hybridization. Synapse 25: 30-36, 1997. Baker GB Urichuk LJ McKenna KF Kennedy SH Metabolism of monoamine oxidase inhibitors Cellular and molecular neurobiology. 19(3): 411-426, 1999. Jauch R Griesser E Oesterhelt G Arnold W Meister W Ziegler WM Guntert TW Biotransformation of moclobemide in humans. Acta Psychiatr Scand 82 (Suppl 360): 87-91, 1990. Waldmeier PC Amrein R Schmid-Burgk W Pharmacology and pharmacokinetics of brofaomine and moclobemide in animals and humans. In Kennedy SH (ed), Clinical Advances in Monoamine Oxidase Inhibitor Therapies, American Psychiatric Press, Washington, DC, 33-59, 1994. FDA patient safety news: "FDA approves Emsam-first drug patch for depression http://www.youtube.com/watch?v=xXVKa_X3n5U . Mian A Serotonin Syndrome and Neuroleptic Malignant Syndrome, Division of Emergency Medicine, London Health Sciences Centre and St. Joseph's Care London (London, Ontario Canada) http://www.youtube.com/watch?v=TKdUqWGAgTU . Mills K.C., Bora K.M. Chapter 172. Atypical Antidepressants, Serotonin Reuptake Inhibitors, and Serotonin Syndrome. In J.E. Tintinalli, J.S. Stapczynski, D.M. Cline, O.J. Ma, R.K. Cydulka, G.D. Meckler (Eds), Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. 2011. Mills KC Serotonin syndrome. A clinical update. Crit Care Clin 13(4): 763-783, Oct, 1997. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352: 1112-1120, 2005. Erratum in: N Engl J Med 356: 2437, 2007. Sun-Edelstein C, Tepper SJ, Shapiro RE: Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf 7: 587-596, 2008. Isbister GK, Buckley NA, Whyte IM: Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 187: 361-365, 2007 (review).