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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.
DEPRESSIVE DISORDERS: AIMS OF TREATMENT 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. Reference 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.
Asad Tamizuddin Nizami
Institute of Psychiatry
Rawalpindi Medical College
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
Recurrent thoughts of death
• 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
• 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
R a n d o m C o m m u n it y S a m p le
3 3 .6 2 %
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 )
Percentage of major diagnostic
categories during four years in IOP
journal of CPSP (2001)
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
• 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.
• 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
Dan J. Stein, Brain-Derived Neurotrophic Factor: The Neurotrophin Hypothesis of
• 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
• 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
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
Kroenke K, Spitzer RL, Williams JB, et al. Arch Fam Med. 1994;3:774-779.
In primary care, physical symptoms are often the chief complaint in
In one study 69% of
as their chief
N = 1146 Primary care patients with major depression
1. Simon GE, et al. N Engl J Med. 1999;341(18):1329-1335.
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
Both serotonin and nor epinephrine mediate a broad spectrum of
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.
Serotonin5HT and Nor epinephrineNE in the brain
Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.
• Dysregulation of Serotonin (5HT)
and Norepinephrine (NE) in the
brain are strongly associated with
• Dysregulation of 5HT and NE in the
spinal cord may explain an
increased pain perception among
• Imbalances of 5HT and NE may
explain the presence of both
emotional and physical symptoms
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.
Research suggests that unexplained pain can be
the best indicator of depression, especially among
Stewart RB, Blashfield R, Hale WE, et al. J Fam Pract. 1991;32:497-502.
Ongoing untreated somatic depression lead to
structural changes in the central nervous system
and augments the risk of persistent pain’’
Areas of the brain which are involved in memory
and decision making undergo structural changes
due to stress, which cause long term imbalances in
• Prefrontal cortex
Undergo changes in
size and function in
• Dentate gyrus continues
to produce new neurons
in adult life
• this is suppressed by
acute and chronic stress
• restored by
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
Comorbid Mood and Anxiety Disorders
of Patients with PTSD1 48%
to 65% of Patients 50%
with Panic Disorder2
(Social Anxiety Disorder)
of Patients with 34-70%
Patients with GAD5
of Patients 67%
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
Aims Of Treatment
STEPS: Antidepressant Selection
Drug-drug interaction potential
Acute and long term
Onset of action
Treatment and prophylaxis
Need for monitoring
• TCAs : Amitriptyline, Doxepine, Trimipramine,
Clomipramine and other.
• SSRI : Fluvoxamine, Fluoxetine, Paroxetine,
Sertraline, Citalopram, Escitalopram
• RIMA :(Reversible inhibitor of MAO type A)
• SNRI : (Reuptake inhibition of NA/5-HT )
• NaSSA : (5-HT2 and 5-HT3 antagonist,H1 antagonist.)
• DSA : (5-HT2 antagonist and 5-HT reuptake inhibitor)
• NARI (SNRI) : (Selective NA reuptake inhibitor)
Adverse events—a significant cause of
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.
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
Adverse Events Are A Major Cause of Early
Dropout with SSRI Treatment
Most common early adverse events resulting in dropouts (> 5%)
N = 672; SSRIs included paroxetine or fluoxetine
Bull SA, et al. Ann Pharmacother. 2002;36:578–584.
Nausea is one of the most common side
• 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
• 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
• 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
• Choose a medication that is effective and
generally well tolerated across multiple
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.