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  • Some symptoms (e.g. appetite, attention) seem to be mediated more by one neurotransmitter than the other. Some other symptoms (e.g. anxiety) seem to be mediated by either. There are other symptoms (e.g. aches and pain) that seem to be mediated more consistently by a combination of both the neurotransmitters.
  • Serotonin and Norepinephrine in Depression1
    Serotonin and norepinephrine are believed to be key neurotransmitters in the etiology of depression
    From the raphe nuclei and locus ceruleus, 5-HT and NE, respectively, send projections up to the prefrontal cortex and limbic system where emotional depressive symptoms are thought to be mediated.
    Additionally, there are also 5-HT and NE-rich tracts into the spinal cord, which are thought to modulate pain perception.
    1. Adapted from Stahl SM. J Clin Psych. 2002; 63: 382-383.
    Once depressive disorders are diagnose, the initial objectives of treatment, in order of priority are to:
    Reduce & ultimately remove all signs and symptoms of the depressive disorder.
    Restore occupational and psychosocial roles/functions to the asymptomatic state.
    Minimize the risk of relapse and recurrence.
  • Nonadherence to antidepressant therapy is a major obstacle in the effective treatment of anxiety disorders and depression.
    A study by Maddox, et al, that analysed dropout rates over a 12-week period in patients who were prescribed antidepressant agents revealed that 52% of patients had discontinued their medication at the 10–12-week period; of these patients, 58% had dropped out due to adverse events.
    Over one half of patients who dropped out reported that their physicians did not know they had stopped their therapy.
    As might be expected, the worse the side effects, the less time for which the patient will take their medications, suggesting that the occurrence of side effects is an important reason for noncompliance.
  • Adverse events have been the leading reason patients do not comply with their SSRI therapy. Compliance improves if patient receives an effective medication and is informed of targeted duration of therapy. In one large scale study examining adherence to antidepressant therapy, 43% of patients who stopped their treatment prematurely did so as a result of adverse events. The most common early adverse events resulting in dropouts were nausea, headache, drowsiness, and an increased feeling of anxiety.
    Bull SA, Hunkeler EM, Lee JY, et al. Discontinuing or switching selective serotonin-reuptake inhibitors. Ann Pharmacother. 2002;36:578–584.
  • As previously discussed, data from studies by Lin, et al and Maddox, et al suggest that adverse events reported with antidepressant therapy are associated with poor compliance, compromised long-term efficacy and premature termination of treatment.
    Thus, the rationale for the development of Seroxat/Paxil CR was to minimise early-onset nausea in order to help improve compliance and reduce premature termination of treatment.
  • We hope that this presentation will support you in being even more successful in your important efforts to help persons who suffer from depression and associated anxiety symptoms.


  • 1. Depressive Illness Asad Tamizuddin Nizami Assistant Professor Institute of Psychiatry Rawalpindi Medical College
  • 2. Major Depressive Episode A marked change from previous functioning for at least two weeks with 5 or more of the following symptoms: ▫ ▫ ▫ ▫ ▫ ▫ ▫ ▫ ▫ Depressed Mood (Irritability/anger in adolescents) Markedly diminished interest or pleasure Significant change in appetite and/or weight Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or excessive guilt Diminished concentration Recurrent thoughts of death
  • 3. Epidemiology • Depression is the fourth most important contributor to the global burden of disease • The point prevalence for depression is 1.9% for males and 3.2% for females. • 5.8% of males and 9.5% of females will develop a depressive episode within a 12-month period. • Every year 5-8% of the adult population gets a depression . • Lifetime risk for a severe depression amounts to 12-16%. Marianne C. Kastrup, Armando Báez Ramos . Global mental health- secondary publication Danish Medical Bulletin - No. 1. February 2007. Vol. 54 Pages 42-3
  • 4. In Pakistan…………. R a n d o m C o m m u n it y S a m p le 3 3 .6 2 % M en W om en 1 0 % (M u m fo rd 2 0 0 0 )- 3 3 % (J a v e d 1 9 9 4 ) 2 8 .8 % (R a b b a n i ) - 6 6 % (M u m fo rd 1 9 9 7 )
  • 5. Percentage of major diagnostic categories during four years in IOP journal of CPSP (2001)
  • 6. Etiology of Depression - Genetics • Indirect evidence suggests that the glycogen synthase kinase-3beta (GSK3beta) gene might be implicated in major depressive disorder (MDD). A recent study identified a link between the GSK3 beta polymorphism and the structural brain changes in major depressive disorder.(2) • A meta-analysis yielded little evidence that the serotonin transporter genotype alone or in interaction with stressful life events was associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.(3) • • 2. Inkster B et al. Association of GSK3Beta polymorphism with structural brain changes in major depressive disorder. Arch Gen Psychiatry. 2009 Jul;66(7):721-8. 3. Risch N et al. JAMA. 2009 Jun 17;301(23):2462-71. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.
  • 7. Neurobiology • In recent years the monoamine theory of depression has given way to a molecular and cellular theory that suggests that antidepressants work by increase in brain levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF). • Basic laboratory work has documented the importance of neurotrophins in neuronal survival and synaptic plasticity.which lead to structural brain changes i.e hippocampal atrophy seen in depression(1) Dan J. Stein, Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology
  • 8. Neurobiology • BNDF plays a role in a range of neurodegenerative, neuroinflammatory, and neurodevelopmental disorders, as well as in some psychiatric and substance use disorders. • Decreased hippocampal BDNF mRNA and cell atrophy are, for example, seen in several animal models of depression. • Depression is associated with decreased hippocampal volume, and depressed patients have decreased hippocampal BDNF. • Chronic stress leads to hippocampal cell loss and to downregulation of BDNF Dan J. Stein, Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of Psychopathology
  • 9. Interestingly………….. • In general practice 1 in 5 new consultations are for pain symptoms for which no specific cause is found. • The pain symptoms of 1/3 of all patients seen in medical clinics remain medically unexplained at the time of discharge.
  • 10. • • • • • • Research has indicated 34% of patients with joint or limb pain, 38% of patients with back pain, 40% of patients with headache, 46% of patients with chest pain, and 43% of patients with abdominal pain had Depression. Kroenke K, Spitzer RL, Williams JB, et al. Arch Fam Med. 1994;3:774-779.
  • 11. In primary care, physical symptoms are often the chief complaint in depressed patients In one study 69% of diagnosed depressed patients reported unexplained physical symptoms as their chief compliant1 N = 1146 Primary care patients with major depression 1. Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335.
  • 12. Is there a connection between pain & depression…….. • There is a Neurochemical overlapping in the phenomena of pain complaints and depression. • Serotonin (or 5-HT) and norepinephrine have emerged as 2 neurotransmitters that are involved in both pain and depression.
  • 13. Both serotonin and nor epinephrine mediate a broad spectrum of depressive symptoms Serotonin (5-HT) Depressed Mood Norepinephrine (NE) Sex Anxiety Concentration Appetite Vague Aches and pain Interest Aggression Irritability Motivation Thought process References: 1. Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge University Press 2000. 2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. 3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35. 4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.
  • 14. Serotonin5HT and Nor epinephrineNE in the brain Limbic System Prefrontal Cortex Raphe Nuclei (5-HT source) Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996. Locus Ceruleus (NE Source)
  • 15. • Dysregulation of Serotonin (5HT) and Norepinephrine (NE) in the brain are strongly associated with depression • Dysregulation of 5HT and NE in the spinal cord may explain an increased pain perception among depressed patients1-3 • Imbalances of 5HT and NE may explain the presence of both emotional and physical symptoms of depression. Adapted from References: 1. Stahl SM. J. Clin Psych. 2002;63:203-220. 2. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114. 3. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. Descending Pathway Descending Pathway Ascending Pathway Ascending Pathway
  • 16. Research suggests that unexplained pain can be the best indicator of depression, especially among the elderly. Stewart RB, Blashfield R, Hale WE, et al. J Fam Pract. 1991;32:497-502.
  • 17. Ongoing untreated somatic depression lead to structural changes in the central nervous system and augments the risk of persistent pain’’
  • 18. Areas of the brain which are involved in memory and decision making undergo structural changes due to stress, which cause long term imbalances in hormonal regulation”
  • 19. • Hippocampus • Prefrontal cortex • Amygdala Undergo changes in size and function in depression
  • 20. • Dentate gyrus continues to produce new neurons in adult life • this is suppressed by acute and chronic stress and • restored by antidepressant treatment
  • 21. The loss of neurons in hippocampus due to stress is reversible if the stress is terminated at the end of 3 weeks Stress also suppresses neurogenesis and causes dendritic shrinkage
  • 22. Comorbid Mood and Anxiety Disorders Lifetime Comorbidity of Patients with PTSD1 48% to 65% of Patients 50% with Panic Disorder2 Posttraumatic Stress Disorder Social Phobia Panic Disorder Major Depression GAD (Social Anxiety Disorder) OCD of Patients with 34-70% Social Phobia4,6 of 39%-8% Patients with GAD5 of Patients 67% with OCD3 Kessler et al. Arch Gen Psychiatry, 1995 2. DSM-IV 3. Rasmussen.. 1 Psychopharmacol Bull, 1988 4. Van Ameringen et al. J Affect Disord, 1991 5. Brawman-Mintzer, Lydiard RB. J Clin Psychiatry, 1996 6. Stein et al, Am J Psychiatry, 2000
  • 24. Treatment Options • Antidepressants • Combination Therapies • Psychotherapy • ECT
  • 25. STEPS: Antidepressant Selection • Safety Drug-drug interaction potential • Tolerability Acute and long term • Efficacy Onset of action Treatment and prophylaxis • Payment Cost-effectiveness • Simplicity Dosing Need for monitoring
  • 26. Antidepressants Groups • TCAs : Amitriptyline, Doxepine, Trimipramine, Clomipramine and other. • SSRI : Fluvoxamine, Fluoxetine, Paroxetine, Sertraline, Citalopram, Escitalopram • RIMA :(Reversible inhibitor of MAO type A) Moclobemide • SNRI : (Reuptake inhibition of NA/5-HT ) Venlafaxine
  • 27. Antidepressants Groups • NaSSA : (5-HT2 and 5-HT3 antagonist,H1 antagonist.) Mirtazapine • DSA : (5-HT2 antagonist and 5-HT reuptake inhibitor) Nefazodone • NARI (SNRI) : (Selective NA reuptake inhibitor) Reboxetine
  • 28. Adverse events—a significant cause of treatment discontinuation Poor tolerability in early therapy Drop out of SSRI therapy Lin EHB et al. Medical Care 1995; 33:67–74. Maddox JC et al. J Psychopharmacol 1994; 8:48–53.
  • 29. Early drop out – other evidence • Early drop out is common among patients taking antidepressants: ▫ 28% by week 4* ▫ 43% by week 8* ▫ 52% by week 12* * Maddox JC et al. J Psychopharmacol 1994; 8:48-53
  • 30. Adverse Events Are A Major Cause of Early Dropout with SSRI Treatment Most common early adverse events resulting in dropouts (> 5%) Nausea Headache Anxiety Drowsiness N = 672; SSRIs included paroxetine or fluoxetine Bull SA, et al. Ann Pharmacother. 2002;36:578–584.
  • 31. Nausea is one of the most common side effects • SSRIs have been associated with early GI adverse events, resulting in: ▫ poor compliance ▫ compromised long-term efficacy ▫ premature termination of treatment1,2 • Nausea is a leading cause of premature treatment discontinuation for the SSRIs and serotonin norepinephrine reuptake inhibitors3 • Clinical trials in major depression with paroxetine IR (n = 6145) ▫ most common event associated with withdrawal on paroxetine IR was nausea (3.2% vs. 1.1% on placebo). • Paroxetine CR was developed to minimise early-onset nausea through a shifting of the drug absorption site (lower in GI tract) 1 Lin EHB et al. Medical Care 1995; 33:67–74. 2 Maddox JC et al. J Psychopharmacol 1994; 8:48–53. 3 Golden RN et al. J Clin Psychiatry 2002; 63:577-584
  • 32. Summary • Patients have a high rate of non-adherence with SSRIs due to adverse events • First few weeks of therapy are critical • Monitor medication compliance during this time period • Choose a medication that is effective and generally well tolerated across multiple indications
  • 33. Role of Psychotherapy? • Psychotherapy either alone or in combination with medication, has been shown to be effective in the treatment of comorbid pain and depression • Some studies have found that the combination of medical and psychotherapeutic treatments provides better results than medication alone. Murphy GE, Simons AD, Wetzel RD, Lustman PJ. Arch Gen Psychiatry. 1984;41:33-41.
  • 34. Thank you