D R I M R A N WA H E E DC O N S U LTA N T P S YC H I AT R I S T
W W W. B H A M P S YC H . C O M F E B R UA RY 2 9 2 0 1 2
The Neurobiology of Depression
Presentation Outline
ContextMonoamine hypothesisHPA AxisHPT AxisGrowth hormoneStructural and functional changesThe role of neurotrophic factorsThe relationship between pain and
depressionThe role of antidepressants
Major Depressive Disorder may have Systemic Consequences
Adapted from Musselman DL, et al. Arch Gen Psychiatry 1998;55(7):580-592.
Complex Biological Factors
Neurotransmitter systemsHormonal axesGeneticsStructural and functional changes in brain
circuitsNeurotrophic factorsComplex intersection between
neurotransmitters, hormones and regions of the brain controlling sleep, motivation, empathy and emotion, etc.
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
HPA Axis
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.
HPA Axis in Depression
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
Time (PM)
0
50
100
150
200
250
2:45 3:30 4:00 4:303:00 3:45 4:15
Cort
isol
(nm
ol/
L)
Prolonged remission (N=20)
Depressive relapse (N=12)
Control (N=24)
*P=.029 compared with control
*
Aubry JM, et al. J Psychiatr Res. 2007;41:290–294.
Dex/CRH=dexamethasone/corticotropin-releasing hormone; MDD=major depressive disorder.
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.)
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.
Functional and Structural Changes
Associated with MDD
Prefrontal cortex2
Amygdala2
Hippocampus5
Nucleus accumbens4
Anterior cingulate cortex3
Insular cortex1
Areas of the Brain Implicated in Depression
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.
Decreased Activity in DLPFC and dACC in Patients with MDD
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
Areas of increased activation in patients with MDD at rest (red) and decreased activation (blue) compared with controls
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.
Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.
Tota
l Hip
poca
mpa
l Vol
ume
( mm
3 )
Days of Untreated Depression
Hippocampal Volume Decreases as Number of Days Depressed Increases
R2=0.28; p=.0006N=38
Brain Atrophy in Depression
Bremner JD, et al. Am J Psychiatry 2000;157(1):115-118.Reprinted with permission from JD Bremner.
Atrophy of the Hippocampus in Depression
Normal Depression
ANOVA=analysis of variance; MOFC=medial orbitofrontal cortices; VMPFC=ventromedial prefrontal cortex.
Patients with MDD May Have Smaller Medial Orbitofrontal Cortices than Controls
Patients with MDD had 32% smaller MOFC (VMPFC) than controls
Orb
itofr
on
tal
cort
ical
(gyr
us
rect
us)
volu
me (
mm
3)
*
*P=.02 vs comparison by ANOVA
MOFC
Bremner JD, et al. Biol Psychiatry. 2002;51:273–279.
Image reprinted with permission from Elsevier
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<.001Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156–1165.
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.
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 BDNFSupport 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.
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.
1000
1600
2000
100
Without SA
BD
NF
(p
g/m
L)
1800
1400
1200
800
600
400
200
With SA
Patients with MDD with or without SA
*P<.001*
*
1000
1600
2000
100
Normalcontrol
First episode
BD
NF
(p
g/m
L)
1800
1400
1200
800
600400
200
Recurrentepisode
*P<.001
*
Patients with MDD with first episode or with recurrent
episode
Normalcontrol
Recurrent Depression and Suicidal Attempts May Be Associated with Lower BDNF Levels
Plasma BDNF levels were measured in 77 patients with MDD and 95 normal controls.
Lee BH. J Affect Disord. 2007;101:239–244.
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder; SA=suicide attempt.
Successful Antidepressant Treatment can be Associated With BDNF Increase
Adapted from Fig 1; Shimizu E, et al. Biol Psychiatry 2003;54(1):70-75.
Pla
sma B
DN
F (
ng
/mL
)
Control
(n=50)Depressed-
Treatment Naïve(n=16)
Depressed-Treated(n=17)
• Mixed group of antidepressants used for treatment. • HAM-D17=27.810.2 and 18.811.4 for untreated and treated groups respectively
p=.024.
*P<.01 vs control or treated
*
SD + 11.4 SD + 9.6 SD + 12.3
Depression and Pain
Physical Symptoms in Psychiatric Patients
Data from Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and normals. Am J Psychiatry 1973;130:102–105
Psychiatric Healthy Symptom Patients %Subjects %
Tiredness, lack of energy 85 40Headache, head pains 64 48Dizziness or faintness 60 14Feeling of weakness in parts of body 5723Muscle pains, aches, rheumatism 5327Stomach pains 51 20Chest pains 46 14
Prevalence of Associated Painful Symptoms in Patients with Depression
Studies addressed both depression and painful symptoms, including: Headaches Back pain Neck pain Extremity/joint pain Chest pain Pelvic pain Abdominal pain General pain
Mean prevalence data from 14 studies focusing on painful
symptoms in patients with depression
MDD withoutpainful
symptoms35%
MDD withpainful
symptoms65%
Prevalence was not influenced by psychiatric versus primary care settings
Depressed patients
Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445.
MDD=major depressive disorder.
Some Key Areas of the Brain that May Play a Role in Both MDD and Pain
Prefrontal cortex
Amygdala
Hippocampus
Anterior cingulate cortex
Insular cortex
Depression & Pain: Similar Dysregulation
Stress and Depression1,2 Pain3
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.
red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axis
The Role of Antidepressants
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
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.
Antidepressant Use can be Associated with Normalization in Brain Activity
Increased activity: DLPFC, dACC, posterior cingulate Decreased activity: sgACC, VMPFC, amygdala, hippocampus, insula
Areas of increased activation in patients with MDD after antidepressant treatment (red) and decreased activation (blue) compared with baseline.
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695.
ACC=anterior cingulate cortex; DLPFC=dorso-lateral prefrontal cortex; VMPFC=ventromedial prefrontal cortex.
2.0-
0.5-
1.5-
1.0-
-0.5-
0-
Relationship Between Change in BDNF Levels, Duration of Treatment and Treatment Response in MDD Patients
Meta-regression based on 10 case control and 13 clinical trial studies assessing 1,504 subjects
Study analyzed (weighted by inverse variance)
BDNF changes versus depression improvement
Ch
an
ge i
n B
DN
F –
eff
ect
siz
e
0 62 4
Cohen’s d for depression
r = 0.65; P=.02
r = 0.52; P=.01
0 80
20
40
60
2.0-
0.5-
1.5-
1.0-
-0.5-
0-
BDNF changes versus days of improvement
Period of treatment (days)
Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11:1169–1180.
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder.
Ch
an
ge i
n B
DN
F –
eff
ect
siz
e
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 depressionSome evidence of link between depression and
painDepression may be neurotoxic – therefore
important to diagnose early and treat ‘aggressively’