A lecture delivered in the West Midlands by Dr Imran Waheed, Consultant Psychiatrist, on The Neurobiology of Depression. For further information visit www.bhampsych.com

1. The Neurobiology of Depression
DR IMRAN WAHEED
CONSULTANT PSYCHIATRIST
WWW.BHAMPSYCH.COM
FEBRUARY 29 2012

2. Presentation Outline
 Context
 Monoamine hypothesis
 HPA Axis
 HPT Axis
 Growth hormone
 Structural and functional changes
 The role of neurotrophic factors
 The relationship between pain and depression
 The role of antidepressants

4. Major Depressive Disorder may have
Systemic Consequences
Adapted from Musselman DL, et al. Arch Gen Psychiatry 1998;55(7):580-592.

5. Complex Biological Factors
 Neurotransmitter systems
 Hormonal axes
 Genetics
 Structural and functional changes in brain circuits
 Neurotrophic factors
 Complex intersection between neurotransmitters,
hormones and regions of the brain controlling sleep,
motivation, empathy and emotion, etc.

6. Monoamine Hypothesis
 Posits that depression is caused by reduced monoamine
function in the brain
 Iproniazid and imipramine had antidepressant effect and
later shown to enhance central 5-HT and NA transmission.
 Reserpine depletes monoamine stores and produces
depressive symptoms.
 ADs increase monoamine transmission e.g. SSRIs inhibit
reuptake, MAOIs inhibit degradation
 However, cause of depression is more complex than central
reduced monoamine function
 MAOIs and SSRIs cause immediate increase in
monoamines yet do not immediately alleviate symptoms

7. HPA Axis

8. HPA Axis
 HPA axis overactivity is one of the best replicated
findings in the neurobiology of depression
 Fifty percent of depressed patients exhibit
nonsuppression of cortisol secretion after administration
of the dexamethasone ; appears that glucocorticoid
receptors may become dysfunctional in depression.
 IV administration of exogenous CRF causes depressed
patients to exhibit a blunted ACTH response compared
with that in healthy subjects; likely to be due to
downregulation of CRF receptors in the pituitary,
secondary to persistent increased CRF secretion.
 Hypercortisolaemia is associated with neurotoxicity and
reduced hippocampal neurogenesis.

9. HPA Axis in Depression

10. Lack of HPA Normalization May Predict Relapse in Remitted
Patients with MDD (Dex/CRH Neuroendocrine Test)
 38 remitted patients with MDD followed up for 12 months
250
Prolonged remission (N=20)
Depressive relapse (N=12)
Cortisol (nmol/L)
200
Control (N=24)
150
*
100
50
*P=.029 compared with control
0
2:45 3:00 3:30 3:45 4:00 4:15 4:30
Time (PM)
Dex/CRH=dexamethasone/corticotropin-releasing hormone; MDD=major depressive disorder.
Aubry JM, et al. J Psychiatr Res. 2007;41:290–294.

11. HPT Axis
 Blunting of the circadian rhythm of thyroid hormone
secretion, with the absence of the normal nocturnal peak
of thyroid-stimulating hormone (TSH) secretion.
 Some depressed patients demonstrate elevated CSF TRH
concentrations.
 The hypersecretion of TRH may lead to downregulation
of TRH receptors on thyrotropic cells of the anterior
pituitary, which accounts for the widely documented
blunted TSH response to exogenous TRH (this is
somewhat diagnostically nonspecific because it is often
observed in manic and alcoholic patients as well.)

12. Growth Hormone
 Growth hormone (GH) is secreted by the anterior
pituitary and plays a pivotal role in enhancing
somatic growth; its secretion is stress responsive.
 Depressed patients demonstrate a blunting of the
diurnal rhythm of GH secretion, especially the
nighttime peak.
 This blunting may be due to the interrupted sleep
that accompanies depression.
 A blunted GH response to provocative stimuli, such
as clonidine use, stress, and hypoglycemia, has also
been noted in depressed patients.

13. Functional and Structural Changes
Associated with MDD

14. Areas of the Brain Implicated in Depression
Prefrontal
cortex2
Insular
cortex1
Anterior
cingulate cortex3
Hippocampus5 Nucleus accumbens4
Amygdala2
1. Kennedy SE, et al. Arch Gen Psychiatry. 2006;63:1199–1208. 2. Drevets WC. Curr Opin Neurobiol. 2001;11:240–249.
3. Whittle S, et al. Neurosci Biobehav Rev. 2006;30:511–525. 4. Schlaepfer TE, et al. Neuropsychopharmacology.
2008;33:368–377. 5. Gaughran F, et al. Brain Res Bull. 2006;70:221–227.

15. Decreased Activity in DLPFC and dACC in
Patients with MDD
Areas of increased activation in patients with MDD at rest (red) and
decreased activation (blue) compared with controls
Increased activity: lateral orbital prefrontal cortex, ventromedial prefrontal cortex,
amygdala, thalamus, caudate
Decreased activity: dorsolateral prefrontal cortex (DLPFC), insula, pregenual and dorsal
anterior cingulate cortex (dACC), superior temporal gyrus
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.

16. Hippocampal Volume Decreases as Number of
Days Depressed Increases
6000
Total Hippocampal Volume ( mm3)
R2=0.28; p=.0006
5500 N=38
5000
4500
4000
3500
3000
2500
0 1000 2000 3000 4000
Days of Untreated Depression
Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.

17. Brain Atrophy in Depression
Atrophy of the Hippocampus in Depression
Normal Depression
Bremner JD, et al. Am J Psychiatry 2000;157(1):115-118.
Reprinted with permission from JD Bremner.

18. Patients with MDD May Have Smaller Medial
Orbitofrontal Cortices than Controls
800
*P=.02 vs comparison by ANOVA
Orbitofrontal cortical (gyrus rectus)
700
Comparison subjects (N=20)
600 Major depression (N=15)
volume (mm3)
500
MOFC
400
*
300
200
100
Image reprinted with permission from Elsevier 0
 Patients with MDD had 32% smaller MOFC (VMPFC) than controls
ANOVA=analysis of variance; MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex.
Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.

19. Decline in Gray Matter Volume in MDD Patients
Compared to Healthy Controls
 3-year prospective study comparing 38 patients with 30 healthy controls
 Significant decline in gray matter density was noted in hippocampus, amygdala,
anterior cingulate cortex, and dorsomedial prefrontal cortex
 Threshold was set at P<.001
Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165.

20. Key Replicated Brain Imaging Findings
 Most brain imaging studies have shown abnormalities in
these key areas: amygdala, hippocampus, prefrontal
cortex, anterior cingulate cortex, and orbitofrontal
cortex1–3
 Many studies have found prefrontal cortical hypoactivity
at baseline improved after treatment4
 Many studies have found limbic hyperactivity (especially
cingulate) at baseline normalized after treatment4
 More recent studies have focused on network
relationships
(limbic, prefrontal) and dynamic changes over time2,4–6
 There is great heterogeneity among patients; scanning is
not predictive or individually diagnostic
1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al.
Neuron. 2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:
377–384. 6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209.

21. Neurotrophic factors
 Volumetric decreases in the hippocampus and other
forebrain regions in depressed patients have
supported hypothesis for depression involving
decrements in neurotrophic factors.
 Main focus has been BDNF
 Support for the „BDNF hypothesis‟ has come from a
literature showing that several forms of stress reduce
BDNF-mediated signalling in the hippocampus,
whereas chronic treatment with antidepressants
increases BDNF-mediated signalling.

22. The Role of Brain-Derived Neurotrophic Factor
 Brain-derived neurotrophic factor (BDNF) and other neurotrophic factors are
involved in cell health or growth as well as cell apoptosis (death) in an activity-
dependent manner
 Neurotrophins such as BDNF may be critical for growth and function of the
nervous system,1 as well as for learning and memory2
 BDNF is expressed throughout the brain in neurons and glia3
 Monoamine neurons such as serotonin (5-HT), norepinephrine (NE), and dopamine
(DA), as well as γ-aminobutyric acid (GABA) and glutamate neurons
 Monoamines may be involved in the regulation of the synthesis and release of BDNF
 Downregulation of neurotrophins may occur in depression,1-2 anxiety,4 and pain5
 Treatment of MDD may restore BDNF function1,2,6-7
1. Castren E, et al. Curr Opin Pharmacol. 2006;6:1–4. 2. Duman RS, et al. Biol Psychiatry. 2006;59:1116–1127.
3. Charney DS, et al. Sci STKE. 2004;225:1–10. 4. Chen B, et al. Science. 2006;314:140–143. 5. Duric V, et al. Neuroscience.
2005;133:999–1006. 6. Ivy AS, et al. Pharmacol Biochem Behav. 2003;75:81–88. 7. Gervasoni N, et al.
Neuropsychobiology. 2005;51:234–238.

23. Recurrent Depression and Suicidal Attempts May Be
Associated with Lower BDNF Levels
Patients with MDD with first Patients with MDD with
episode or with recurrent episode or without SA
2000 2000
*P<.001 * *P<.001
1800 1800
*
1600 1600
1400 1400
BDNF (pg/mL)
BDNF (pg/mL)
1200 1200 *
1000 1000
800 800
600 600
400 400
200 200
100 100
Normal First Recurrent Normal Without SA With SA
control episode episode control
 Plasma BDNF levels were measured in 77 patients with MDD and 95 normal controls.
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder; SA=suicide attempt.
Lee BH. J Affect Disord. 2007;101:239–244.

24. Successful Antidepressant Treatment can be
Associated With BDNF Increase
35
*P<.01
30 vs control or treated
Plasma BDNF (ng/mL)
25
20 *
15
SD + 11.4 SD + 9.6 SD + 12.3
10
5
0
Control Depressed- Depressed-Treated
Treatment Naïve (n=17)
(n=50)
(n=16)
• Mixed group of antidepressants used for treatment.
• HAM-D17=27.8 10.2 and 18.8 11.4 for untreated and treated groups respectively p=.024.
Adapted from Fig 1; Shimizu E, et al. Biol Psychiatry 2003;54(1):70-75.

25. Depression and Pain

27. Physical Symptoms in Psychiatric Patients
Psychiatric Healthy
Symptom Patients % Subjects %
Tiredness, lack of energy 85 40
Headache, head pains 64 48
Dizziness or faintness 60 14
Feeling of weakness in parts of body 57 23
Muscle pains, aches, rheumatism 53 27
Stomach pains 51 20
Chest pains 46 14
Data from Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and
normals. Am J Psychiatry 1973;130:102–105

28. Prevalence of Associated Painful Symptoms in Patients with Depression
Depressed patients  Studies addressed both depression
and painful symptoms, including:
 Headaches
MDD MDD with
without painful  Back pain
painful symptoms
symptoms
 Neck pain
65%
35%  Extremity/joint pain
 Chest pain
 Pelvic pain
 Abdominal pain
Mean prevalence data from 14 studies
focusing on painful symptoms  General pain
in patients with depression
 Prevalence was not influenced by psychiatric versus primary care settings
MDD=major depressive disorder.
Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445.

29. Some Key Areas of the Brain that May Play a Role in
Both MDD and Pain
Prefrontal
cortex
Insular
cortex
Anterior
cingulate cortex
Hippocampus
Amygdala

30. Depression & Pain: Similar Dysregulation
Stress and Depression1,2 Pain3
red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axis
Adapted from: 1. Raison, et al. Trends in Immunol. 2006;27:24–23. 2. Nestler EJ, et al. Neuron. 2002;34:13–25.
3. Blackburn-Munro G, et al. J Neuroendocrinol. 2001;13:1009–1023.

31. The Role of Antidepressants

32. Are Antidepressants Neuroprotective?
 Animal studies show that antidepressants can induce
neurogenesis
 Out of 38 women with depression, those who had spent the
least time on antidepressants had greater shrinkage of the
hippocampus
 More evidence from human studies is needed

33. HPA Axis and Treatments
 Laboratory animal studies show that antidepressants and
ECT alter glucocorticoid receptors, enhancing the
binding of glucocorticoids to these receptors.
 Interestingly, this effect of antidepressants on
glucocorticoid receptors takes 2 weeks, about the same
duration of time needed for antidepressants to begin
improving depressive symptoms.
 Persistent nonsuppression in the DST as well as
persistent elevation of CSF CRF concentrations despite
symptomatic improvement of depressive symptoms with
treatment, is associated with risk for early relapse.

34. Antidepressant Use can be Associated with
Normalization in Brain Activity
Areas of increased activation in patients with MDD after antidepressant treatment (red)
and decreased activation (blue) compared with baseline.
Increased activity: DLPFC, dACC, posterior cingulate
Decreased activity: sgACC, VMPFC, amygdala, hippocampus, insula
ACC=anterior cingulate cortex; DLPFC=dorso-lateral prefrontal cortex; VMPFC=ventromedial prefrontal cortex.
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.

35. Relationship Between Change in BDNF Levels, Duration of
Treatment and Treatment Response in MDD Patients
BDNF changes versus BDNF changes versus
depression improvement days of improvement
Change in BDNF – effect size
Change in BDNF – effect size
2.0- r = 0.65; P=.02 2.0- r = 0.52; P=.01
1.5- 1.5-
1.0- 1.0-
0.5- 0.5-
0- 0-
-0.5- -0.5-
0 2 4 6 0 20 40 60 80
Cohen‟s d for depression Period of treatment (days)
 Meta-regression based on 10 case control and 13 clinical trial studies assessing 1,504 subjects
 Study analyzed (weighted by inverse variance)
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder.
Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11:1169–1180.

36. Conclusion
 Depression is more complex than just a “chemical
imbalance”
 Good evidence that there is interplay between
neurotransmitters, hormones, immunological
factors, structural deficits, etc.
 Pain is a common symptom in depression
 Some evidence of link between depression and pain
 Depression may be neurotoxic – therefore important
to diagnose early and treat „aggressively‟