Conversations at The Royal public lecture series
By The Royal's Dr. Pierre Blier, MD, Ph.D
Endowed Chair and DirectorMood Disorders Research
Institute of Mental Health Research
University of Ottawa, Ontario
Canada Research Chair, Psychopharmacology
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Depression: the brain, the mind, the family and work
1. Depression: the brain, the mind,
the family, and work
Pierre Blier, MD, Ph.D
Endowed Chair and Director
Mood Disorders Research
Institute of Mental Health Research
University of Ottawa, Ontario
Canada Research Chair, Psychopharmacology
2. Global burden of diseases-World Health Organization
DALYs: disability adjusted life years; WHO 2008 report
3. Global burden of diseases-World Health Organization
DALYs: disability adjusted life years; WHO 2008 report
4. Global burden of diseases-World Health Organization
+50%
+30%
DALYs: disability adjusted life years; WHO 2008 report
5. Mortality and severe mental illness
>15,000 patients with bipolar disorder diagnosis studied (Sweden)1
Standardized mortality ratio (all causes) in bipolar patients was 2.5
for males, 2.7 for females (values >1.0 indicate greater risk than
general population)
Most frequent cause of death for bipolar patients
•
Cardiovascular disease: 31%
•
Suicide: 19%
•
Cancer: 14%
Patients with severe schizophrenia, bipolar disorder, and
depression lose 25 or more years of life expectancy, with most of
the premature deaths due to cardiovascular disease2, 3,4
1. Osby et al. Arch Gen Psychiatry 2001;58:844-850.
2. Angst et al. J Affect Disord 2002;68:167-181.
3. Newcomer and Hennekens. JAMA 2007;298:1794-1796.
4. Colton and Manderscheid. Prev Chronic Dis 2006;3:A42.
6. Depression worsens outcome of
many medical conditions
Depression worsens morbidity and mortality after myocardial
infarction1,2
Depression increases morbidity and mortality in patients with
congestive heart failure3,4
Depression increases risk of mortality in patients
in nursing homes5
Depression worsens morbidity post-stroke6
Depression may worsen outcomes of cancer,
diabetes, AIDS, and other disorders7
1. Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.
2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221227.
3. Jiang W, et al. Arch Intern Med. 2001;161:1849-1856.
4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205.
5. Rovner BW, et al. JAMA. 1991;265:993-996.
6. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319.
7. Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl
1):80-84.
7. Depression Has an Impact on Mean Health Scores
More Than Other Chronic Conditions
“Depression had the largest effect on worsening mean health scores”
100
*p<0.0001
p<0.01
N=245,404
†
90.6 = No chronic condition
90
80
*
1
1
80
*
2
1
3
1
80
79
*
70
60
*
4
1
*
1
79
73
Depression only
†
†
†
1
2
3
65
66
67
†
4
59
Conditions
1.Asthma
2.Angina
3.Arthritis
4.Diabetes
0
One Chronic Condition
Depression +
One Chronic Condition
*Depressed respondents had lowest mean score among all chronic conditions (p<0.0001).
†
Depressed respondents with another chronic condition had lower mean health scores than
respondents with the chronic condition alone (p<0.01).
Moussavi et al. Lancet 2007;370(9590):851-58.
8. DEPRES-STUDY
78,463 ADULTS
I
I
5,414 (6.9%)
MAJOR DEPRESSIVES
100%
31%
28%
24%
5%
NO CONSULTATION
NO DRUG TREATMENT
NON-ANTIDEPRESSANT DRUG
INADEQUATE DOSE OF AN
ANTIDEPRESSANT DRUG
12%
ADEQUATE DOSE OF AN
ANTIDEPRESSANT DRUG
INT. CLIN. PSYCHOPHARMACOL. 12 : 19, 1997
9. Only one patient in three fully
recovers after a first medication trial
Antidepressant Effects After 6-8 Weeks
Partial Response
33%
Full Remission
33%
33%
No response
Kennedy et al, Human Psychopharmacology 2001
11. The many faces of major depression
DSM-IV criteria
35 y.o. female
+ Depressed mood
+ Hypersomnia
+ Increased appetite/weight
+ Psychomotor retardation
+ No energy
+ Suicidal ideation
70 y.o. male
- Marked loss of interest/pleasure
- Insomnia
- Decreased appetite/weight
- Psychomotor agitation
- Impaired concentration/decision
- Inappropriate guilt
12. Evidence of Hippocampal Atrophy
and Loss in MDD Patients
Compared to controls,
patients with depression
had smaller hippocampal
volumes1
Images reprinted with permission of JD Bremner.
1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.
2. Sheline YI, et al. J Neurosci. 1999;19:5034-5043.
3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93:3908-3913.
4. Sheline YI, et al. Am J Psychiatry. 2003;160:1516-1518.
Decreased hippocampal
volume may be related to
the duration of depression2-4
13. Hippocampal Volumes Are Decreased In Depressed Patients with
Multiple Episodes (ME)but Not In The First Episode (FE)
4000
Control
FE
Control
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
FE
1000
Right
Left
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
1000
Control
MacQueen et al, PNAS, 2003
ME
Control
ME
14. Alteration of Brain Volume in Depression
Phillips et al, J Clin Psychiiatry 2012
15. Antidepressants and Neurotrophic Factors May Help
Restore Communication in Depression
Normal
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Depressed
Treated
Reprinted with permission from Elsevier.
16. Functional Overlap Between Aminergic
Systems: Features of Depression
NE
5-HT
Energy
Interest
Anxiety
Irritability
Impulsivity
Mood, emotion,
cognitive function
Motivation
Drive
Dopamine
Sex
Appetite
Aggression
27. Actual Dropouts
Treatment groups
Causes
Fluoxetine Fluoxetine Bupropion Venlafaxine
+ Mirtazap + Mirtazap + Mirtazap
Adverse events
XX
X
X
Lack of efficacy
XX
X
X
Lost to follow up
X
X
XX
XXX
4/26
(15%)
3/26
(12%)
Protocol violation
Total: 16/105
(15%)
X
5/28
(18%)
4/25
(16%)
34. Our experience with ketamine
Monitoring of pulse, EKG, blood pressure, and
EKG, and O2 saturation
230 infusions in 16 patients taking antidepressants
6 remitters, 5 responders, 5 non-responders
Duration of action: starting from 60 minutes to 12
hours, for a total time of 24 hours to 3 weeks
0.5 mg/kg, iv/40 min > 0.2 mg/kg, iv/bolus
Marked anti-suicidal ideation effect
No evidence of neurotoxicity or dependence
* Blier, Zigman & Blier, Biological Psychiatry 2013
35. A case of remission
37 y.o. female, married, 4 kids, works as teacher
Physical History: not contributory
Psychiatric History
• 2 episodes of depression
• Paroxetine 30 mg w/ response
Zigman & Blier, J Clin Psychopharmacol 2013
36. Current episode
Relapse in Dec 2009, no trigger
Feb 2010 – Venlafaxine up to 300 mg, no response
Nov 2010 - Started NIH study, MADRS 39
• Up to Escitalopram 40 mg + bupropion XL 450 mg
Mar 2011 – End of phase 1 (12 weeks), MADRS 36
Mar 2011 – Suicide attempt by overdose
37. Current Episode
Mar -> Sept 2011
• Trials of Duloxetine + Quetiapine XR, Duloxetine +
Aripiprazole, Duloxetine + Risperidone
• Persistent moderate to severe depressive symptoms
Oct 2011
• Lithium added to Duloxetine + Risperidone
• “I feel better than I have in 2 years”
Nov 2011 – Feb 2012
• Relapsed after 1 month
• Lithium restarted, Duloxetine switched to Moclobemide
• Persistent moderate depressive symptoms
38. Current Episode
Feb 2012 –
• Lithium tapered to discontinuation because of loss of
benefits
Patient presents to office 2 weeks later in severe
distress, intense suicidal ideation, MADRS 48
Offered admission + ECT or trial of ketamine
39. Ketamine infusion #1
Given 0.5 mg / kg ketamine over 40 min
Reported feeling “numb”, “dopy” and “as if floating”
No psychotic symptoms
Subjectively:
Pre
Post (60min)
Dysphoria
10/10
3/10
Anxiety
8/10
0/10
Suicidal ideation
9/10
0/10
40. Ketamine infusion # 2
Relapsed after 2 weeks
Given 0.5 mg / kg ketamine over 40 min
Subjectively:
Pre
Post (60min)
Dysphoria
10/10
1/10
Anxiety
7/10
0/10
Suicidal ideation
3/10
0/10
41. Follow up and Medications
Patient had a third ketamine infusion with the same
response as the first two
Sustained remission in the Fall of 2012
• Nortriptyline 125 mg/day
• Lithium 600 mg/day
• Vyvanse 20 mg/day
Partial relapse in January 2013
• Nortriptyline switched to Anafranil 75 mg/day
• Return to normal within a few days
42. Take home messages
We all have a role to play in decreasing the stigma of
depression to get people in treatment
Depression must be treated aggressively because it
worsens all other medical disorders and shrinks the brain
In most cases, depression does not take months to bring
to remission because there are efficacious treatments
There are new treatments on the horizon
Notes de l'éditeur
References
1. Osby et al. Arch Gen Psychiatry 2001;58:844-850.
2. Angst et al. J Affect Disord 2002;68:167-181.
3. Newcomer and Hennekens. JAMA 2007;298:1794-1796.
4. Colton and Manderscheid. Prev Chronic Dis. 2006;3:A42.
When depression is accompanied by certain nonpsychiatric medical conditions (eg, coronary artery disease, diabetes), the outcome of these concurrent medical disorders is likely to be worse than if depression were not present
Specifically, depression has been shown to worsen outcomes after myocardial infarction and increase the risk of cardiac mortality1,2
Recent studies also have confirmed that the presence of major depression or depressive symptoms is associated with increased morbidity and mortality in patients with congestive heart failure3,4
The presence of depression may increase the risk of mortality in patients in nursing homes5
Depression may worsen outcomes after stroke6 and among patients with cancer, diabetes, AIDS, and other disorders7
Sources:
Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.
Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227.
Jiang W, et al. Arch Intern Med. 2001;161:1849-1856.
Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205.
Rovner BW, et al. JAMA. 1991;265:993-996.
Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319.
Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84.
PURPOSES OF THE SLIDE
To show how depression by itself can have an impact on patient health compared with other chronic conditions.
Emphasize the impact depression can have when comorbid with other chronic conditions.
KEY POINTS
Recently published data from the World Health Organization (WHO) World Health Survey (WHS) show the impact of depression upon public health, whether alone or in combination with other chronic diseases.
The WHS studied nearly 250,000 adults from 60 countries worldwide for health, health-related outcomes, and their determinants.
Respondents with a single chronic condition had mean health scores that were significantly different from having no disease, but not different from each other. As the chart shows, mean health scores of those patients with depression were lower than those of patients with any of the other major chronic conditions alone (as shown in the white circles).
The impact of depression was even more severe when it was comorbid with asthma, angina, arthritis, or diabetes.
The authors emphasized that depression had the largest effect on worsening mean health scores compared with other chronic conditions.
The Mean Health score was transformed to a 0–100 scale, with 0 indicating worst health and 100 indicating best health.
REFERENCE
Moussavi et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 2007;370(9590):851–58.
Key Message: Less than 40% of patients on antidepressant therapy will achieve remission. Almost two-thirds of patients will remain symptomatic.
Content:
Review of antidepressant response rate in a database of 209 patients at the Clarke Institute for Psychiatry in Toronto
39% of patients had a full response to treatment, i.e., remission
32% had a partial response
In total, 71% of patients responded to antidepressant therapy
On the other hand, only 40% of patients achieved remission, and over 60% remained symptomatic, with only partial or no response to therapy
These are the people most vulnerable to recurrence and relapse
No drug or gender differences were seen in this study
Patients with MDD (N=215) received a fixed dose of fluoxetine 20 mg for 8 weeks. Presence of residual symptoms not predicted by baseline demographic characteristics or Axis I and Axis II comorbid conditions.
Adding a second medication to an ongoing treatment should always be considered, especially if a partial response has been obtained. At this point, it was not deemed necessary to separate the two strategies that can be used when adding a second agent. These are: the combination and the augmentation strategies. The former refers to adding another antidepressant medications, whereas the latter refers to adding a second pharmacological agent which is not antidepressant when used on its own. It is nevertheless important to mention that this strategy can still be used even if no therapeutic benefit was obtained with the first medication. This rests on the notion that even if a drug produces no clinical improvement, it does not mean that no biological effects were obtained; it may only signify that the biological alterations were not sufficient to trigger clinically detectable changes. For instance, from the early reports on the effectiveness of lithium augmentation, it was observed that some lithium responsive patients had not shown any benefit with their tricyclic drug regimen.
Some of the disadvantages of adding a second agent can be offset by judiciously choosing the second drug. For example, if a patient has marked insomnia, a sedative agent like mirtazapine could be used; if a patient present significant lack of energy, an activating agent like bupropion could be used. If cost is a major issue, this could be minimized by using a drug like lithium, or even a tricyclic antidepressant.
KEY POINTS
Atrophy of the hippocampus, a region of the brain involved in conscious memory, may be associated with depression.
Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. These studies demonstrated that stress and antidepressant treatment may exert opposing actions on the expression of specific neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition.1
Most notable are studies of BDNF. The functional significance of altered neurotrophic factor expression was highlighted by studies demonstrating that stress and depression can lead to neuronal atrophy and cell loss in key limbic brain regions implicated in depression, including the amygdala, prefrontal cortex, and hippocampus (which expresses high levels of receptors for glucocorticoids, the major stress reactive adrenal steroid).1
Several studies have associated depression with decreased hippocampal volume.2,3 Furthermore, this reduction in volume has been related to the duration of depression.3-5
BACKGROUND
The hippocampus is one of several limbic structures that have been implicated in mood disorders. Included in the functions of hippocampal circuitry are control of learning and memory and regulation of the hypothalamic-pituitary-adrenal (HPA) axis, both of which are altered in depression. The hippocampus has connections with the amygdala and prefrontal cortex, regions that are more directly involved in emotion and cognition and thereby contribute to other major symptoms of depression.1
Bremner et al studied 16 patients with a history of depression based on the Structured Interview for DSM-IV, finding hippocampal volume loss and memory deficits.2
In a sample of 24 women age 23 to 86 years with histories of recurrent major depression, Sheline et al found that post-depressives scored lower in verbal memory, suggesting that the hippocampal volume loss was related to an aspect of cognitive functioning. The study also found duration of depressive episode to be a predictor of hippocampal volume loss.3
REFERENCES
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116-1127.
Bremner JD, Narayan M, Anderson ER, et al. Hippocampal volume reduction in major depression. Am J Psychiatry. 2000;157(1):115-118.
Sheline YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. Neurosci. 1999;19:5034-5043.
Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93:3908-3913.
Sheline YI, Gado MH, Kraemer HC, et al. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516-1518.
KEY POINTS
Antidepressants and neurotrophic factors such as BDNF play in restoring communication within depressed patients.
Molecular and cellular studies of stress, depression, and antidepressants have moved the field of mood disorder research beyond the monoamine hypothesis of depression. These studies demonstrated that stress and antidepressant treatment may exert opposing actions on the expression of specific neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition. The requirement for long-term, chronic antidepressant treatment has led to the hypothesis that alterations in functional and structural plasticity may be necessary for a therapeutic response.1
The panel on the left shows a normal hippocampal pyramidal neuron and its innervation by glutamatergic, monoaminergic, and other neurons. Its regulation by BDNF (derived from hippocampus or other brain areas) is also shown.2
Severe stress can cause several changes in these neurons, including a reduction in their dendritic branching, and a reduction in BDNF expression (which could be one of the factors mediating the dendritic effects). The reduction in BDNF is thought to be mediated partly by excessive glucocorticoids, which could interfere with the normal transcriptional mechanisms that control BDNF expression and therefore damage hippocampal pyramidal neurons.2
Antidepressants are thought to produce the opposite effects: they increase dendritic branching and BDNF expression of these hippocampal neurons. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus, and therefore may ameliorate certain symptoms of depression.2
BACKGROUND
Neuronal atrophy and reduced neurotrophic factor expression that are observed in preclinical models, as well as decreased expression of BDNF in depressed subjects, suggest that there could be structural alterations in mood disorder patients. Brain imaging studies have addressed this question and demonstrate a reduction in the volume of the hippocampus of depressed subjects.3-5 In addition, the reduction of hippocampal volume may be reversed by antidepressant treatment.3,6
REFERENCES
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116-1127.
Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13-25.
Sheline Y, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. 2003. Am J Psychiatry. 160:1-3.
Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56:140-145.
Duman RS. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 2004;5:11-25.
Vermetten E, Vythilingam M, Southwick SM, et al. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry. 2003;54:693-702.
Key Point
Several neurotransmitters are involved in regulating mood
Background
The effects of NE, 5-HT, and dopamine overlap in the CNS
All 3 neurotransmitters are involved in mood, emotion, and cognition
Thus, depressive symptoms may result from dysregulation of any or all of these neurotransmitter systems
Reference
Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge University Press; 2000:135-197.
Antipsychotic Agents
Side-Effect Profiles
The side-effect profiles of conventional antipsychotics (taken as a group) and currently available atypical antipsychotics in young adult schizophrenic patients are provided on the above slide
All atypical antipsychotic medications are associated with considerably lower rates of extrapyramidal symptoms (EPS) and TD than the older conventional antipsychotics. Higher doses (>2 mg/day) of risperidone may be associated with higher EPS rates. Higher doses of the other atypical antipsychotics may also be associated with higher EPS rates. Therefore, it is important to start with low doses and slowly titrate upward to achieve the lowest effective dose
The seizure threshold lowering effect of clozapine and olanzapine is of some concern, as is sedation for clozapine, olanzapine, and quetiapine
KEY POINTS
There are complex signaling cascades that may be influenced by antidepressants.
5-HT and/or NE can help regulate the expression of BDNF.
The illustration shows the functional interactions among monoamine neurotransmitters, glutamate, and neurotrophic signaling cascades.
Elevation of glucocorticoids and excitatory neurotransmitters, due to chronic mood disorders, may impair neuroplasticity and cellular resilience.1
Use of antidepressants can regulate the expression of BDNF, leading to enhancement of neuroplasticity and cellular resilience.2,3
5-HT and/or NE activate intracellular cascades that can independently lead to activation of transcription factor (CREB) and eventual synthesis of BDNF. BDNF interacts with TrkB receptor to enhance neuroplasticity and neurogenesis. By facilitating synthesis of a neuroprotective factor, Bcl-2, BDNF helps improve cellular resilience.4
Genetic factors and life stress may contribute to neurochemical alterations, impairments in cell resilience, reductions in brain volume, and cell death and atrophy often observed in depression.5
A growing body of evidence suggests that agents that act upon, for instance, cAMP response element-binding protein (CREB), norepinephrine (NE), serotonin (5-HT), glutamate (Glu), brain-derived neurotrophic factor (BDNF), and Bcl-2—a protein that promotes cell viability or death—may have antidepressant actions.5
BACKGROUND
Charney and Manji’s review aims to shed light on the psychological and neurobiological determinants of depression, as progress is being made toward specifying the role of genetic factors, psychosocial stressors, and gene-environment interactions in depression.5
Key abbreviations: α2AR = alpha2 adrenergic receptor; AC = adenylyl cyclase; AMPAR = α-amino 3-hydroxy-5-methylsoxazole propionate receptor; GC = guanylyl cyclase; GR = glucocorticoid receptor; MAPK = mitogen-activated protein kinase; NMDAR = N-methyl-D-aspartate receptor; TrkB = tyrosine receptor kinase receptor B.
REFERENCES
Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry. 2003;53(8):707-742.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104-9110.
Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75.
Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7(5):541-547.
Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Science STKE. 2004;225 re5:1-10.
In the following series of slides, the essentials of mirtazapine will be explored. Its unique properties on CNS receptors, and its basic safety and dosing will be noted. Studies of efficacy and tolerability versus standard comparator drugs are examined.
When depression is accompanied by certain nonpsychiatric medical conditions (eg, coronary artery disease, diabetes), the outcome of these concurrent medical disorders is likely to be worse than if depression were not present
Specifically, depression has been shown to worsen outcomes after myocardial infarction and increase the risk of cardiac mortality1,2
Recent studies also have confirmed that the presence of major depression or depressive symptoms is associated with increased morbidity and mortality in patients with congestive heart failure3,4
The presence of depression may increase the risk of mortality in patients in nursing homes5
Depression may worsen outcomes after stroke6 and among patients with cancer, diabetes, AIDS, and other disorders7
Sources:
Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.
Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221-227.
Jiang W, et al. Arch Intern Med. 2001;161:1849-1856.
Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205.
Rovner BW, et al. JAMA. 1991;265:993-996.
Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319.
Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84.