Medical Pharmacology: Drugs Used to Manage Depression

Antidepressant Medication Overview, continued¹⁰⁷
- Many antidepressants have been characterized or classified on the basis of their ability to inhibit the serotonin transporter (SERT).¹³¹
  - These agents are referred to as SSRIs (serotonin-specific reuptake inhibitors).¹³¹
    - An underlying rationale is a suggestion that serotonergic neurotransmission abnormalities are part of the pathologies in depression as well as anxiety, suicidal behavior and obsessive-compulsive disorder, (OCD).
  - This section and the earlier sections address possible mechanisms to explain an observation that SSRIs (as well as other antidepressant agents) require an extended period of administration prior to observing clinical improvement.
Clinical issues in antidepressant drug therapy I
- Antidepressant drugs must be administered for a somewhat extended period prior to an expectable clinical effect.¹⁰⁷
  - The principle underlying mechanism or mechanisms for this delay remains a contemporary neuropharmacological research question.
  - However, one consequence of this delay in onset is that, for some patients judged to be at high risk of suicide exhibiting agitation, electroconvulsive therapy with its more rapid onset of clinical effect may be an appropriate therapeutic choice.
  - The time to clinical effect for antidepressant agents exhibits a range, with a minimum of about 3-4 weeks, although some patients may require treatment for greater than two months to achieve an adequate response.^107,2
    - For a particular antidepressant agent, if an eight week trial is insufficient to achieve an acceptable clinical effect, an alternative antidepressant which he exhibits a different mechanism of action should be considered.
    - The first agent used would likely be initiated at a low dose, which would be gradually increased over a 7-10 day period, achieving at that time the initial dose target.²
      - If after a 3-4 week interval, absent complete recovery and dose-limiting side effects, the dosage may be increased further, ultimately to the upper end of the therapeutic range.
      - If the patient exhibits suicidal tendencies, particular attention must be given early in treatment since "behavioral activation" may occur earlier than observable mood improvement, thus providing a window in which patients have sufficient energy to act on suicidal impulses.²
- Concerning antidepressant efficacy in different age groups, consistent beneficial effects in adolescents and children have not been shown in all clinical trials.²
  - Perhaps in those trials factors such as study design, medication compliance or other considerations are responsible for difficulty in showing benefit.
  - Moreover, antidepressant agents continued to be widely used in depressed adolescents and children.
    - Antidepressants may themselves increase risk of self-injury, at least in a transiently and it appears that the overall risk of suicide in this group, adolescents and children, is reduced by antidepressant treatment.
  - In elderly depressed patients, antidepressants are considered quite useful; however, dosage adjustments may be required due to altered hepatic clearance and protein binding, i.e. pharmacokinetic changes.²
- In some cases the antidepressant medication response is only partial. In that case other options may be considered including adding other medications to the primary antidepressant drug.²
  - For example, if the primary antidepressant belongs to the tricyclic antidepressant category, lithium carbonate and thyroid hormone (especially T₃) have been identified as beneficial.
  - These "augmentation" approaches should be continued for at least three weeks in the absence of clinical response. ²
    - The likelihood that a previously non-responding patient will respond in this setting is about 50%. With respect to the SSRIs, T₃ augmentation may be effective, although the effectiveness of lithium remains to be fully elucidated.
    - Another augmentation technique, not involving drugs, is sleep deprivation.
      - Antidepressant effects following only one night of wakefulness occurs in about 65% of patients. This technique, referred to as "recovery sleep" may however be associated with rapid relapse.
  - Refractory depression may be managed using a combination of an antidepressant drug classified as noradrenergic (e.g. buproprion or desipramine) and another agent classified as serotonergic (e.g. the serotonin specific reuptake inhibitor, fluoxetine). ²
    - If an SSRI is used in combination with a tricyclic antidepressant, levels of the TCA should be determined because of drug-associated competitive inhibition of the P450 liver microsomal drug metabolizing system, the P450 enzyme isoform particularly important in this example is CYP2D6.
      - Inhibtion of CYP2D6 may lead to excessively high TCA serum levels.
  - Addition of cognitive-behavioral therapy, discussed earlier, to antidepressant treatment may be beneficial as well. ²
    - A particular type of CBT described as "cognitive behavioral analysis system of psychotherapy" may be especially appropriate.²
  - Other approaches that may be considered in refractory depression include the combination of a tricyclic antidepressant and a monoamine oxidase inhibitor (MAOI), a combination which has been associated with acute, potentially serious side effects.
    - There is also some question concerning the efficacy of this combination, a prominent example of which would be phenelzine and imipramine. ²
      - The MAOI is typically initiated first and upon establishment of stable dosing, a low-dose of the tricyclic antidepressant may then be administered.
  - Electroconvulsive therapy (ECT) is also a therapeutic option in refractory cases.²

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 STAR*D 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.