Depression: the brain, the mind, the family and work

1,223 views
977 views

Published on

Conversations at The Royal public lecture series

By The Royal's Dr. 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

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,223
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide
  • 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.
  • Depression: the brain, the mind, the family and work

    1. 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. 2. Global burden of diseases-World Health Organization DALYs: disability adjusted life years; WHO 2008 report
    3. 3. Global burden of diseases-World Health Organization DALYs: disability adjusted life years; WHO 2008 report
    4. 4. Global burden of diseases-World Health Organization +50% +30% DALYs: disability adjusted life years; WHO 2008 report
    5. 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. 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. 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. 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. 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
    10. 10. Residual Symptoms Following Acute Remission of Depression Percentage of Subjects 50 Threshold 38% 40 30 Subthreshold 44% 28% 20 10 0 Mood Diminished Weight Sleep PsychoDisturbance motor Pleasure or Interest Fatigue Guilt Concentration Symptoms of Depression Nierenberg AA, Keefe BR, Leslie VC, et al. J Clin Psychiatry. 1999(Apr);60(4):221-225 © 2009 Canadian Psychiatric Association. All rights reserved. (N=215) Suicidal Ideation
    11. 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. 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. 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. 14. Alteration of Brain Volume in Depression Phillips et al, J Clin Psychiiatry 2012
    15. 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. 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
    17. 17. Functional connectivity 5-HT2A for NE neurons 5-HT2C for DA neurons
    18. 18. LOCUS COERULEUS 5-H T (+) 5-HT (-) RAPHE α2 (-) SSRI? 5-HT α 1 α2 (-) 1 α T 1A -H 5 (-) POSTSYNAPTIC NEURON (-) 5-HT β1 (+) α 2 (-) α 2 1A HT 5-
    19. 19. SSRIs decrease NE transmission (Szabo and Blier, 2000; Kawahara et al, 2007) Normal : Norepinephrine (NE) Long-term treatment with a SSRI Amygdala Locus coeruleus 9 2 * 1 0 90 Cont 54 Citalopram Fmoles/sample Spikes/sec 3 6 3 0 * Cont Citalopram
    20. 20. Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) ? (-) 5-HT 2A 5-HT1A (-) 5-HT α ) 1(+ NE α 1 (+) -) α2 (
    21. 21. Inhibitory Effect of Escitalopram (X 14 days) on VTA Dopamine Neuronal Firing Control (11 cells/6 rats) 10 Escitalopram (22 cells/5 rats) 9 8 7 6 5 * * * 3 * 4 2 1 0 Rate (Hz) Bursts/10 sec Spikes/Bursts % Spikes Occurring in Bursts (x10) Dremencov et al, J Psychiat Neurosci 2009
    22. 22. Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) (-) 5-HT 2C (-) 5-HT 2A 5-HT1A (-) 5-HT α1 NE α 1 (+) -) α2 (
    23. 23. Atypical Antipsychotic Medication: Meta-analysis of Response Rates Odds Ratios of Response Rates With Atypical and Placebo Trials Nested by Drug Olanzapine trials Shelton 2001 Shelton II 2005 Corya 2006 Thase 2006 Thase II 2006 OR (Fixed) 95% CI Subtotal 1.83 [1.18, 2.82]; Z=2.71, p=0.007 Subtotal 1.61 [1.24, 2.09]; Z=3.56, p=0.0004 Subtotal Quetiapine trials 1.39 [1.05, 1.84]; Z=2.30, p=0.02 Subtotal Risperidone trials Mahmoud 2007 Keitner 2009 Reeves 2008 2.07 [1.58, 2.72]; Z=5.28, p=0.00001 Khullar 2006 Mattingly 2006 McIntyre 2006 Earley 2007 El-Khalili 2008 Aripiprazole studies Berman 2007 Marcus 2008 Berman 2008 1.69 [1.46, 1.95]; Z = 7.00, p< 0.00001 Test for overall effect: 0.1 0.2 0.5 1 Favors Control Nelson JC and Papakostas GI Am J Psychiatry, 2009 2 5 10 Favors Treatment Double-blind, placebo-controlled add on trials
    24. 24. Acute Study Design Depressed Patients With Unipolar Major Depression Washout + Screening Day Day 0 -7 Day 7 Day 14 Day 21 Day 42 Fluoxetine 20 + Placebo Fluoxetine 20 + Mirtazapine 30 Venlafaxine 75 Venlafaxine 150 Venlafaxine 225 + + + Mirtazapine 30 Mirtazapine 30 Mirtazapine 30 Bupropion 150 + Mirtazapine 30 Blier et al, Am J Psychiat 167:281-8,2010
    25. 25. Effectiveness of drug combinations Fluoxetine (n = 28) HAMD 17 scores (+ SEM) 25 Fluoxetine + Mirtazapine (n = 25) Bupropion + Mirtazapine (n = 26) Venlafaxine + Mirtazapine (n = 26) 20 15 10 * 5 0 1 4 7 10 14 21 28 35 42 Day of treatment * P = 0.011 when comparing the combination groups with fluoxetine Blier et al, Am J Psychiat 167:281-8,2010
    26. 26. Remitters Hamilton-17 Depression Score ≤ 7 Fluoxetine (7/28) 25% Fluoxetine + mirtazapine (13/25) 52%* Bupropion + mirtazapine (12/26) 46% Venlafaxine + mirtazapine (15/26) 58%* Blier et al, Am J Psychiat 167:281-8,2010
    27. 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%)
    28. 28. Remission rates in monotherapy vs combination from treatment initiation Patients (%) achieving remission 100 75 50 25 49 45 SSRI Mirtazapine SSRI 20-30 mg 0.0 21 30 mg 20-30 mg* Blier et al, Eur Neuropsychopharmacol 2009 Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine 20 25 25 Bupropion Venlafaxine 150 mg 225 mg + Mirtazapine 30 mg
    29. 29. Remitters Hamilton-17 Depression Score ≤ 7 (N=88) Dropouts* 1 site Escitalopram (mean: 35 mg/day) 42% 3/31 Bupropion 28% 6/28 52% 3/29 (mean: 375 mg/day) Combination (mean: 33/380) *Mean dropout rate: 13%
    30. 30. Antidepressants modulate interconnected signaling cascades (-) (-) Adapted from: Charney DS, et al. Science STKE. 2004;225 re5:1-10. (-)
    31. 31. Rapid Antidepressant of Ketamine (iv) Zarate et al. Arch Gen Psychiat 63: 856-63, 2006
    32. 32. Rapid Antidepressant of Ketamine (iv) Zarate et al. Arch Gen Psychiat 63: 856-63, 2006
    33. 33. Attenuation of suicidal ideation by ketamine Price et al, Biol Psychiat 66:522-6,2009
    34. 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. 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. 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. 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. 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. 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. 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. 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. 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

    ×