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

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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

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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

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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.

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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

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(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.

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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

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Cohen’s d for depression

r = 0.65; P=.02

r = 0.52; P=.01

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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.

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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’