Improving Outcomes in Major Depression: A Focus on Cognitive Symptoms

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1 Improving Outcomes in Major Depression: A Focus on Cognitive Symptoms Faculty Disclosure Dr. Rakesh Jain: Consultant Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda (Spouse: Lilly, Otsuka, Pamlab); Speakers Bureau Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research Support AstraZeneca, Allergan, Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda. Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing offlabel or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). The off-label use of buspirone, erythropoietin, lisdexamfetamine, lithium, modafinil, tranylcypromine, and triiodothyronine for the treatment of major depressive disorder will be discussed. Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

2 Introduction & Taking a Measure of Major Depression s Impact Depression is Associated with Significant Economic Costs Unipolar depression is the leading cause of global disease burden among mental, neurological, and substance use disorders The total annual cost of depression in Europe was estimated at 118 billion in 2004, which corresponds to a cost of 253 per inhabitant $44 billion cost to US employers in 1 year Burden of Disease: Leading Individual Disease/Disorder Contributors Other Conditions 45% Mental Health Disorders 23% Cancer 16% 16% 1. Unipolar depression 2. Ischaemic heart disease 3. Alcohol-use disorders 4. COPD 5. Trachea / bronchus / lung cancer 6. Hearing loss: adult onset 7. Alzheimer's disease / dementia 8. Cerebrovascular disease Cardiovascular Disease Total DALYs: USA and Canada (%) Data courtesy of World Health Organization DALY = disability-adjusted life-year; COPD = chronic obstructive pulmonary disease. Collins PY, et al. Nature. 2011;475(7354): Sobocki P, et al. J Ment Health Policy Econ. 2006;9(2): Stewart WF, et al. JAMA. 2003;289(23): Depression is a Clinically Heterogeneous Disorder with Emotional, Physical, and Cognitive Symptoms Emotional Sadness Anxiety Irritability Lack of enjoyment Suicidal ideation Hopelessness Guilt Difficulties with: Attention and concentration Short- and long-term memory Decision-making Planning and organization Mental flexibility Word-finding Thinking speed Cognitive Fatigue Eating changes Insomnia Sexual dysfunction Headaches Physical Stomach problems Chest pain American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; World Federation for Mental Health. Depression: A Global Crisis. October 10, Accessed on January 5, Fehnel SE, et al. CNS Spectr. 2013;[Epub ahead of print]. Hammar A, et al. Front Hum Neurosci. 2009;3:26. Bair MJ, et al. Arch Intern Med. 2003;163(20): Clayton A. Effects of Psychiatric Illness and Medication on Sexual Function. July 20, Accessed on January 5, 2016.

3 Symptom Dimensions of MDE Suicidal ideation Fatigue or loss of energy Worthlessness or guilt * Depressed Mood * Anhedonia Psychomotor agitation or Indecisiveness retardation or diminished ability to think Insomnia or hypersomnia Significant appetite or weight changes ALL symptoms are important! Symptoms are often underrecognized and underappreciated every day in clinical practice Each one of these symptoms, by themselves, or in combinations, can become Residual Symptoms MDE = major depressive episode. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Textbook Revision). Arlington, VA: American Psychiatric Association; Point Worthy of Note Cognitive Dysfunction is underrepresented even in DSM-5 criteria (receives only 1criteria out of 9) Patient Perception of Burden from Individual Symptoms of Major Depression

4 Patient Perspective on the Most Common Diagnostic Symptoms of MDD: An Unequal Distribution From a 13-year study following a general population sample in the Baltimore Epidemiologic Catchment Area (N = 1920) Proportion of MDD patients with symptoms during MDEs (n = 100) * Depressed mood Sleep problems Trouble thinking Appetite problems Thoughts of death Lost of interest Tiredness Worthlessness Slowness/restlessness *MDD diagnosis was based on DSM-III-R criteria and symptoms were assessed by the National Institute of Mental Health Diagnostic Interview Schedule. MDD = major depressive disorder. Chen LS, et al. Am J Psychiatry. 2000;157(4): Cognitive Symptoms of Depression Have a Negative Impact on All Aspects of a Patient s Life Cognitive dysfunction and general functioning are linked; both have an impact on clinical outcomes Find it difficult to maintain job performance Loss of focus Loss of productivity Work/ School Life Family/ Personal Life Experience household and financial strain Struggle with a variety of attention related tasks Unable to fully participate in family life Find it difficult to participate in social life Exhibit social irritability Social Life Have problems meeting expectations from society McIntyre RS, et al. Depress Anxiety. 2013;30(6): Hammar A, et al. Front Hum Neurosci. 2009;3:26. Point Worthy of Note Cognitive Dysfunction is impairing, and often lost in the mix with emotional and physical symptoms of MDD

5 Neurobiology of MDD: A Brief Examination of Emergent Data & Clinical Goal Setting in MDD Cognition Related Brain Networks Underpin Symptoms of Major Depression A. Healthy Controls Study integrated findings from 59 functional neuroimaging studies of adults with unipolar depression using a narrative approach High activation CCN B. Depressed Individuals Suppressed activation AN Deactivation AMN 2 distinct neurocognitive networks, the AMN and the CCN, are central to the symptomatology of depression Hyperactivation AMN Activation AN Deactivation CCN ACC = anterior cingulate cortex; AMN = autobiographic memory network; AN = affective network; CCN = cognitive control network; dacc = dorsal ACC; dlpfc = dorsolateral prefrontal cortex; ompfc = orbitomesial PFC; racc = rostral ACC. Rayner G, et al. Neurosci Biobehav Rev. 2015;61: How We Humans Create Cognition A Neuropsychiatric Perspective Basal Frontal Ganglia Lobe Thalamus Parietal ACC Cortex Dorsolateral Episodic and PFC semantic memory (space, time, and context) Sub CA1 CA3 DG Hippocampus V/VI I/II ERHC Association PFC Cortex OFC Amygdala PORC Temporal lobe PRHC (semantic memory: storage and retrieval) Cerebellum PRTC = parietal cortex; PFC = prefrontal cortex; ACC = anterior cingulate cortex; OFC = orbital prefrontal cortex; PORC = postrhinal cortex; PRHC = perirhinal cortex; GP = internal globus pallidus; SNr = substantia nigra pars reticulata; VA = ventral anterior thalamic nucleus; MD = medial dorsal thalamic nucleus. PRTC PFC Basal Ganglia Thalamus Segregation, convergence, and crosstalk Dorsolateral PFC ACC OFC Dorsolateral caudate nucleus Nucleus accumbens Ventromedial caudate GPi and SNr VA and MD MD VA and MD Trivedi MH, et al. J Affect Disord. 2014; : Millan MJ, et al. Nat Rev Drug Discov. 2012;11(2):

6 MDD is Associated with Reductions in Volume in Areas of the Brain Associated with Higher Cognitive Functions Axial Sections DLPFC 27% decrease OFC 19% decrease ACC 8%-11% decrease FG 11% decrease Working memory Executive function Strategic planning Decision-making Emotional processing Cognitive flexibility Reward processing Adaptive learning Attention Emotional processing Emotional encoding Social cognition Social cognition Facial recognition n = 102, MDD; n = 34, controls. FG = fusiform gyrus. Grieve SM, et al. Neuroimage Clin. 2013;3: Depressed Patients Display Negative Biases in Attention, Working, and Verbal Memory Eye-tracking studies show that depressed patients preferentially attend to negatively-valenced stimuli while healthy controls show no such biases Depressed patients are slower to disengage from sad stimuli during affective working memory tasks and faster to disengage from happy stimuli while healthy controls display the opposite bias Kellough JL, et al. Behav Res Ther. 2008;46(11): Levens SM, et al. J Exp Psychol Gen. 2010;139(4): Serotonin, Through Multiple 5-HT Receptor Subtypes, Control a Large Number of Mood Related Functions mpfc DR / MnR Cortex Thalamus Hippocampus Amygdala Glu 5-HT 3 5-HT 5-HT 5-HT 4 5-HT 3 5-HT 2A Pyr 5-HT 5-HT Glu 5-HT 1B 5-HT 1A AMPA Glu mglur II/III GABA A GABA B VTA LC 5-HT = serotonin; DR = dorsal raphe; GABA = gamma-aminobutyric acid; Glu = glutamate; LC = locus coeruleus; mglur = metabotropic glutamate receptor; MnR = median raphe; mpfc = medial prefrontal cortex; VTA = ventral tegmental area. Amargós-Bosch M, et al. Cereb Cortex. 2004;14(3): Puig MV, et al. Cereb Cortex. 2004;14(12):

7 Point Worthy of Note The neurobiology of Cognitive Dysfunction in MDD is well characterized, and it involves macrostructures (such as brain networks) to microstructures (individual receptors) The Ultimate Treatment Goal in Depression is Full Functional Recovery Treatment goals in depression have evolved Nearly half of depressed patients who achieve remission do not consider themselves to be in remission Remission Some symptoms may persist Response Many symptoms remain 1990s Definition varies between 1970s studies, but commonly Reduction of symptoms defined as MADRS score 10, or HAM-D (eg, 50% of MADRS or 17 score 7 HAM-D score) Full Functional Recovery Symptoms are essentially absent; patient returns to premorbid functional status Current Expectations not yet formally defined; measures should include clinician ratings, self-reports, and performance testing to assess symptoms and functioning HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale. Zimmerman M, et al. J Affect Disord. 2012;142(1-3): Zimmerman M, et al. J Clin Psychiatry. 2012;73(6): A Focused Examination of the Impact of Cognitive Symptoms and Impairments in MDD

8 Cognitive Dysfunction across Psychiatric Disorders Major Depression Bipolar Disorder Attention Working Executive Episodic Semantic Visual Verbal Procedural Processing and / or Memory Function Memory Memory Memory Memory Memory Speed Vigilance +(+) (+) + ++(+) ++(+) Schizophrenia (+) ASD (+) 0 / ADHD / OCD +++( ) +(+) / / PTSD +++( ) +(+) +(+) (+) 0 + Panic disorder +++( ) + 0 / / + 0 / GAD Parkinson s Disease Alzheimer s Disease ++ ++(+) / (+) +(+) +(+) (+) = consistently present but not pronounced; ++ = a common marked characteristic; +++ = a core, severe, and virtually universal characteristic of the disorder; () = an intermediate magnitude of effect; = increased; 0 / + = poorly documented; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder. Millan MJ, et al. Nat Rev Drug Discov. 2012;11(2): All 3 Domains of Depression (Emotional, Cognitive, and Physical) are Highly Prevalent Residual Symptoms of Depression Percentage of time that patients met DSM-IV criteria per symptom cluster During MDE During remission Time (%) Conradi HJ, et al. Psychol Med. 2011;41(6): Incidence of Residual Symptoms Self-Reported Remission Rates Depressive symptoms in remitted depressed outpatients according to HAM-D 17 who do and do not consider themselves to be in remission Mild Severity Threshold Moderate Severity Threshold CUDOS Symptom Self-Reported Self-Reported Not in Self-Reported Self-Reported Not in Remission (n = 77) a Remission (n = 63) b Remission (n = 77) a Remission (n = 63) b n % n % n % n % Depressed mood *** ** Loss of interest ** * Poor appetite ** * Increased appetite Insomnia ** Hypersomnia *** Psychomotor agitation *** ** Psychomotor retardation *** Low energy *** * Guilt *** *** Worthlessness *** *** Impaired concentration *** *** Indecisiveness *** Death wishes * Suicidal thoughts Hopelessness * *P <.05, **P <.01, ***P <.001; a Due to missing data, sample size varied from 75 to 77; b Due to missing data, sample size varied from 60 to 63. Zimmerman M, et al. J Affect Disord. 2012;142(1-3):77-81.

9 Depressive Symptoms Persist during Periods of Remission and Subsequent Depressive Episodes Importance of all 3 sets of residual symptoms is highlighted: Emotional Symptoms Cognitive Symptoms Physical Symptoms Mean proportion of time symptoms are present during 3-year follow-up period (N = 267) Mean Proportion of Time DSM-IV Symptom Cluster is Present Cognitive problems Core symptoms: depressed mood/ interest Lack of energy Sleeping problems Worthlessness/guilt Eating problems Psychomotor problems Death ideations Weeks of Follow-up Conradi HJ, et al. Psychol Med. 2011;41(6): Inter-relationship between Cognitive Function and General Function in Depression NEUROCOGNITIVE FUNCTION Ability to perform tasks and meet psychosocial demand GENERAL DAILY FUNCTION Disease Course Variables Number of depressive episodes Number of hospitalizations Course of illness Age of onset Years with illness CLINICAL CHARACTERISTICS Disease State Acute Episode Severity of affective symptoms >1/3 suffer in remission Function Poor reintegration at work Employment Social function Readiness for cognitive therapies Baune BT, et al. Psychiatry Res. 2010;176(2-3): Beblo T, et al. Neuropsychol Rev. 2011;21(4): Patients with Depression Often Report Experiencing Cognitive Symptoms Brain is cloudy Key Domains of Cognitive Function Lack of focus Scientific terminology Real-life terminology Patient descriptors Slow motion Tired/Lethargic Concentration difficulties Not listening Lose train of thought Attention deficit Procrastinate Lacking confidence Loss of short- and long-term memory Forgetful Indecisive Fehnel SE, et al. CNS Spectr. 2013;[Epub ahead of print]. McIntyre RS, et al. Depress Anxiety. 2013;30(6): Trivedi MH, et al. J Affect Disord. 2014; :19-27.

10 2 Points Worthy of Note 1. Cognitive Dysfunction can be present during active disease, as well as a residual symptom 2. Also, the 4 areas of Cognitive Dysfunction to note in MDD are 1) Attention 2) Memory 3) Executive Function 4) Psychomotor Speed Now That We Appreciate That Cognitive Dysfunction is Common and Impactful, How Do We Screen for It in Everyday Clinical Practice? Some Practical Tips There are Multiple Ways to Measure Clinical Outcomes in Depression In clinical practice, physicians and patients take a less empirical approach, often with differing priorities Physician Patient Key Treatment Priorities 1. Remission1 2. Avoidance of of relapse1 3. Improvements in in social function1 1. Response 2. Reduction in cognitive symptoms 3. Reduction in anxiety symptoms Criteria for Remission Decrease in negative affect symptoms Increase in positive affect symptoms Return to normal function Zimmerman M, et al. J Clin Psychiatry. 2012;73(6): Zimmerman M, et al. J Affect Disord. 2012;142(1-3):77-81.

11 We Could Just Rely on Standard Depression Rating Scales, BUT They Underestimate Cognitive Difficulties Assessing Residual Cognitive and Physical Symptoms are Poorly Done by Most Depression Rating Scales HAM-D Retardation (slowness of thought and speech, impaired ability to concentrate, decreased motor activity) MADRS Difficulties in concentrating and sustaining thought, which reduces ability to read or hold a conversation BDI I have greater difficulty in making decisions than I used to PHQ Trouble concentrating on things, such as reading the newspaper or watching TV Standard depression scales do not assess all cognitive or physical symptom domains HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale; BDI = Beck Depression Inventory; PHQ = Patient Health Questionnaire. Selection of Neuropsychological Tests Involves Cognitive Domains Known to Be Affected in MDD Primary endpoint (composite score) DSST A measure of executive function, working memory, processing speed, and visuospatial attention RAVLT A measure of verbal learning and memory Executive Function Psychomotor Speed Attention Memory STROOP (a measure of mental [attentional] vitality and cognitive flexibility/response inhibition) Trail Making A (a measure of attention, visual searching, and mental processing speed) Simple Reaction time task (a measure of psychomotor function / speed of processing) Trail Making B (a measure of executive control and cognitive flexibility / set-shifting) Choice Reaction time task (a measure of visual attention and vigilance) DSST = Digit Symbol Substitution Test; RAVLT = Rey Auditory Verbal Learning Test. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4): McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17(10): Mahableshwarkar AR, et al. Neuropsychopharmacology. 2015;40(8):

12 2 Excellent Supplemental Scales to Measure Cognitive Dysfunction: Perceived Deficits Questionnaire (PDQ-5) Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) PDQ-5 The following questions describe problems people may have with their memory, attention, or concentration. Please select the best response based on your experiences during the past 7 days. Patient-reported Total score 0 20 The higher the score, the more frequent the symptoms Fehnel SE, et al. CNS Spectr. 2013;[Epub ahead of print]. Massachusetts General Hospital CPFQ Self-rated scale, sensitive to treatment, short, easy to use clinically 7 items, 4 specifically assess cognition Motivation/interest/enthusiasm Wakefulness/alertness Energy Focus/sustain attention Remember/recall information Find words Sharpness/mental acuity Each item rated 1 (greater than normal) to 6 (totally absent) Higher scores indicate greater impairment Fava M, et al. Psychother Psychosom. 2009;78(2):91-97.

13 Massachusetts General Hospital CPFQ Accessed on January 5, We Can Elevate Our Clinical Practices by Inquiring about the Following Symptoms in Symptomatic, Partial Responder, and Remitted Patients Dear Patient, Are You Having Trouble with Routine, Routine, Routine Assessment for Residual Symptoms is Appropriate 1. Memory problems 2. Poor concentration 3. Expressing thoughts 4. Word finding 5. Slow thinking 6. Problem solving Real World, Clinical Examples of Questions We Clinicians Can Ask Our Patients Some Representative Cognitive Domains Attention/vigilance Working memory Verbal learning and memory Visual learning and memory Reasoning and problem solving Speed of processing Social cognition What is It? Responding correctly to targets while not responding to distractors during a series of rapidly presented stimuli Maintaining and manipulating information in mind for brief (approximately 5-20 seconds) periods of time Remembering verbal information over longer periods of time (minutes to years) Remembering visual information over longer periods of time (minutes to years) The ability to apply strategies effectively Responding quickly and accurately when executing relatively simple tasks Effectively processing social information, such as facial expressions and emotions and the meaning of social interactions Real-World Example Being able to read a book or pay attention to a movie Remembering a phone number just given to you Remembering the items someone told you to purchase at the supermarket Remembering where you put something in a closet Arriving on time for work even though your bus schedule has changed Using a touch-screen computer to serve customers at a fast-food restaurant Knowing by looking at someone whether they are angry at you or not; being able to take someone else s perspective in a conversation Kalkstein S, et al. Curr Top Behav Neurosci. 2010;4: Nuechterlein KH, et al. Am J Psychiatry. 2008;165(2): Sabbe B. Proceedings of the Belgian Royal Academies of Medicine. 2012;1:77-88.

14 Examining Treatment Options: Focus on Both Nonpharmacologic and Pharmacologic Treatment Options First, Let s Examine the Nonpharmacologic Treatment Options Nonpharmacologic Treatments to Improve Cognitive Dysfunction in MDD The following treatments have demonstrated positive studies in improving cognitive dysfunction in MDD Neuropsychological Educational Approach to Remediation (NEAR), a computerized cognitive retraining package (PSSCogReHab) Psychodynamic psychotherapy Sahaj Yoga Meditation Electroconvulsive Therapy Physical Exercise At a cellular level, preliminary research suggests that cognitive training may influence spine density, synaptogenesis, and vascular supply to the brain. Additionally, it may promote glial and metabolic activity, brain-derived neurotrophic factor and hippocampal neurogenesis. Baune BT, et al. Psychiatry Res. 2014;219(1): McIntyre RS, et al. CNS Drugs. 2015;29(7):

15 Running Away from Your Problems Physical Exercise and Cognition Changes in spatial working memory outcomes over 12 weeks of exercise. Participants randomized to receive high dose exercise (16 KKW) performed significantly better on the spatial working memory task with respect to generation of fewer errors on the most complex problems (8 boxes) (P <.04), and showed trends (P <.06) on the 4 box problems as well as the strategy score, which is indicative of effective completion of the task. In contrast, participants in the low dose exercise group generated more errors (P <.04) and showed less efficient use of strategy over time (P <.04). Spatial Working Memory Performance by Group KKW 16 KKW Boxes 6 Boxes 8 Boxes Between Errors Strategy Greer TL, et al. Eur Neuropsychopharmacol. 2015;25(2): Diet and Exercise Change Gut Microbiota and Both Positively and Independently Impact Cognition Mice Study. Examining groups of rats exposed to HFD vs not, and mice allowed to freely exercise vs not. Gut microbiota was studied, along with measures of cognition MDS Dimension 2 ND+ex ND HFD+ex HFD MDS Dimension 1 Multidimensional analysis of diet and exercise reveals orthogonal changes in the gut microbiome. This analysis in multidimensional space demonstrates clear segregation of each of the 4 groups of mice with no overlap between groups. ex = exercise; HFD = high fat diet; ND = no diet. Kang SS, et al. Mol Neurodegener. 2014;9:36. Relative Abundance OTU39-Clostridiales; A Ruminococcaceae R 2 = P = OTU79-Clostridiales; C Ruminococcaceae R 2 = P = Impact of Diet and Exercise are orthogonal ie, independent of each other Freezing Context (%) Relative Abundance OTU82-Clostridiales; B Ruminococcaceae R 2 =.2144 P = D OTU57-Clostridiales; Lachnospiraceae R 2 =.1010 P = Freezing Context (%) 2 Points Worthy of Note 1. Nonpharmacologic treatments for cognitive dysfunction are a growing body of literature 2. How much we exercise and what we eat, does matter even from a cognitive perspective

16 Pharmacologic Treatment Options Question to Ponder: How Can an Antidepressant Have Pro-Cognitive Effects? By positively impacting hot cognition By positively impacting cold cognition Through neurogenesis, particularly in the dentate region of the hippocampus Through reducing cognitive bias that is inherent in major depression Through altering glucose metabolism in various procognitive regions of the brain Through impacting glutamate / GABA balance Baune BT, et al. Psychiatry Res. 2014;219(1): Pharmacologic Approaches for the Treatment of Symptoms following Inadequate Response to SSRIs Treatment- Resistant Depression Early Pharmacologic Approaches 2 Increase Dose 1 Allows time for natural recovery to start and to carry out further assessments Switch 3 Initially, to another SSRI, or a better tolerated newergeneration antidepressant Switch Then to an antidepressant of a different pharmacologic class that may be less well tolerated American Psychiatric Association, Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition Accessed on January 6, 2016.

17 Pharmacologic Approaches for the Treatment of Symptoms following Inadequate Response to SSRIs (continued) Residual Symptoms of Depression Early Pharmacologic Approaches Increase dose Switch within class Switch to another class Further Management 1Add CBT 2Lithium augmentation Augmentation 3 4 Antidepressant combination (mirtazapine with SSRI or SNRI) Atypical antipsychotic augmentation Neuromodulation 5 American Psychiatric Association, Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition Accessed on January 6, Within or Out of Class Treatment Switch in SSRI-Resistant Patients: Which is Superior? Switch A meta-analysis of 4 clinical trials (N = 1496) found a modest yet statistically significant advantage in remission rates when switched to a different class rather than another SSRI Poirier and Boyer, 1999 Lenox-Smith et al, 2001 NNT = 22 Thase et al, 2001 Rush et al, 2006 Favors within-class switch * * Favors across-class switch Combined Risk Ratio *The top box represents the sertraline-venlafaxine pairwise comparison and the bottom box the sertraline-bupropion pairwise comparison. NNT = number needed to treat; SSRI = selective serotonin reuptake inhibitor. Papakostas GI, et al. Biol Psychiatry. 2008;63(7): Real-World Efficacy of Antidepressants Evidence from Second-Line Treatment in STAR*D Switch Response and remission rates in patients following switch from first-line treatment with citalopram Patients (%) Switch 1 Response Remission 0 Citalopram Bupropion Sertraline Venlafaxine n = 2876 n = 239 n = 238 n = 250 At entry: 80% recurrent or chronic depression; mean episodes: 6; mean duration: 25 months Remission defined as QIDS-SR16 score 5 at exit from the indicated treatment step, citalopram group also included those with an exit score of 7 on the 17-item HAM-D. Response defined as 50% reduction in QIDS-SR16 score from entry score at each step. QIDS-SR = Quick Inventory of Depressive Symptomatology Self-Report; STAR*D = Sequenced Treatment Alternatives to Relieve Depression. Trivedi MH, et al. Am J Psychiatry. 2006;163(1): Rush AJ, et al. N Engl J Med. 2006;354(12):

18 Real-World Efficacy of Antidepressants Evidence from Third-Line Treatment in STAR*D Augmentation Switch At entry: 80% of patients had recurrent or chronic depression; mean number of episodes: 6; mean duration: 25 months Proportion of Patients with Remission (%) n=279 n=2876 n=286 n=73 n=69 n=51 n=58 Initial AD Augment 1 Augment 2 Switch 3 AD = antidepressant; T3 = triiodothyronine. Nierenberg AA, et al. Psychol Med. 2010;40(1): Rush AJ, et al. Am J Psychiatry. 2006;163(11): Nierenberg AA, et al. Am J Psychiatry. 2006;163(9): McGrath PJ, et al. Am J Psychiatry. 2006;163(9): Atypical Antipsychotic Augmentation of SSRI Treatment: A Meta-Analysis of Placebo-Controlled Trials Treatment augmentation with an atypical agent resulted in Atypical Response rate 44.2% vs 29.9% for placebo Antipsychotic Augmentation Remission rate 30.7% vs 17.2% for placebo Efficacy risk difference between augmentation with an atypical agent vs placebo translated into NNT of 9 for response NNT of 9 for remission Risk difference for discontinuation due to adverse events with atypical agent vs placebo resulted in an NNH of 17 N = NNH = number needed to harm. Nelson JC, et al. Am J Psychiatry. 2009;166(9): Atypical Antipsychotic Augmentation of SSRI Treatment Adjunctive Aripiprazole Atypical Antipsychotic Augmentation In a multicenter, randomized, double-blind, placebo-controlled study of 362 patients with MDD, remission rates were 26.0% with adjunctive aripiprazole and 15.7% with adjunctive placebo (P =.011) At 6 weeks, the mean change in MADRS total score was significantly greater in patients receiving adjunctive aripiprazole than in those receiving placebo Mean (±SE) Change in MADRS Total Score from End of Prospective Treatment Phase to End of Randomized Treatment Phase Baseline * * -10 * * * Placebo (n = 172) Ariprprazole (n = 181) -12 *P <.001. Berman RM, et al. J Clin Psychiatry. 2007;68(6): Week

19 Common Adverse Effects Responsible for Treatment Discontinuation In an observational study, adverse events were the most common reason cited for SSRI discontinuation after 3 months Patients (%) Most Bothersome Side Effects (N = 406) *Defined as decreased sexual drive and functioning. Goethe JW, et al. J Clin Psychopharmacol. 2007;27(5): Sexual Dysfunction in Patients with Untreated MDD Sexual Dysfunction in Depressed Patients vs Healthy Controls MDD Symptom Severity Correlates with the Degree of Sexual Dysfunction in Untreated MDD Patients Healthy Controls (n=291) Untreated Depression 22 (n=122) Depression Treated with Medication 16 (n=37) Depression Treated without Medication 10 0 (n=41) Total Hamilton Depression Scale Score A meta-analysis of 12 studies revealed a bidirectional association between untreated depression and sexual dysfunction - 6 studies (N = 3285) showed that depression increased the risk of sexual dysfunction by 50% to 70% - 6 studies (N = 11,171) showed that sexual dysfunction increased the risk of depression by 130% to 210% Angst J. Int Clin Psychopharmacol. 1998;13 Suppl 6:S1-S4. Thakurta RG, et al. Indian J Psychol Med. 2012;34(4): Atlantis E, et al. J Sex Med. 2012;9(6): Population (%) Total Sexual Function Score Hot and Cold Cognition: An Emerging Concept in Mental Health Emotional processing; response to negative feedback. Changes in the hot system are more likely to be associated with antidepressant response Emotion-independent; logical thinking and executive control (executive, attention, perception, and psychomotor functions) Roiser JP, et al. CNS Spectr. 2013;18(3):

20 What Do We Mean When We Say Cognitive Problems in Depression? Examining the Different Cognitive Domains Cognition Hot cognition Cold cognition Social cognition Examples Rumination Catastrophic reactions Bias towards negative stimuli (internal/external) Anhedonia (eg, anticipatory anhedonia) Executive function Information processing speed Learning and memory Attention/concentration Theory of mind Mentalization McIntyre RS, et al. CNS Drugs. 2015;29(7): Hot and Cold Cognition Have Different Brain Pathways and Connectivity Connectivity between PFC and Other Brain Regions Cingulate Hippocampal Formation Parietal/Occipital Visual-Association Areas Image provided by Roger S. McIntyre, MD, FRCPC Hot Cognition VMPFC is linked to emotion-based cognition, with associations to emotional processing areas (eg, amygdala) VMPFC Cold Cognition DLPFC is associated with non-emotional cognition, sensory, and motor areas (eg, basal ganglia and parietal cortex) VMPFC = ventromedial prefrontal cortex. Wood JN, et al. Nat Rev Neurosci. 2003;4(2): Motor Structures DLPFC Amygdala Complex Posterior Parietal Heteromodal Area Inferior Temporal Visual-Association Areas Effects of Antidepressants on Cognitive Function in MDD Drug Duloxetine Escitalopram Fluoxetine Paroxetine Vortioxetine Study Design/ Cognitive Domain Elderly N = wks Adults N = wks Elderly N = 18 4 wks Adults N = wks Elderly N = year Elderly N = year Elderly N = wks Composite cognitive score (v) Attention (v) (v) (v) (v) Working memory (v) (v) Executive function (v) (v) Processing speed (v) (v) Memory (v) (v) (v) Verbal learning (v) (v) (v) = function still remained lower than that of controls. Cassano GB, et al. J Clin Psychiatry. 2002;63(5): Herrera-Guzmán I, et al. Psychiatry Res. 2010;177(3): McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17(10): Katona C, et al. Int Clin Psychopharmacol. 2012;27(4): Raskin J, et al. Am J Psychiatry. 2007; 164(6): Savaskan E, et al. Int J Neuropsychopharmacol. 2008;11(3):

21 Mechanism of Action of Various Antidepressants 1 target (reuptake inhibition) SSRI 2 pharmacologic targets (reuptake inhibition) SNRI SERT SERT NAT Vilazodone Vortioxetine SERT 5-HT 1A SERT 5-HT 1A 2 pharmacologic targets (receptor activity + reuptake inhibition) 6 pharmacologic targets (receptor activity + reuptake inhibition) 5-HT 1B 5-HT 1D 5-HT 3 Uptake inhibitor Agonist Partial agonist Antagonist 5-HT 7 NAT = noradrenaline transporter; SERT = serotonin transporter; SNRI = serotonin-norepinephrine reuptake inhibitor. Nutt DJ. J Psychopharmacol. 2009;23(4): Bang-Andersen B, et al. J Med Chem. 2011;54(9): Comparing 2 Different Mechanisms of Action: Antidepressants in Patients with Depression Improvement from baseline compared with placebo at week 8 in patients 65 years DSST and RAVLT Exploratory Endpoints Standardized Effect Size vs Placebo Week 8: FAS, ANCOVA, Cohen s d Vortioxetine 5 mg/day (n = 156) Duloxetine 60 mg/day (n = 151) * * * * DSST RAVLT acquisition RAVLT delayed recall *P <.05, P <.01 vs placebo; nominal P-values; n numbers are APTS. ANCOVA = analysis of covariance; APTS = all-patients-treated set; DSST = Digit Symbol Substitution Test; FAS = full analysis set; RAVLT = Rey Auditory Verbal Learning Test. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4): Effects on Cognitive Function Cannot Be Solely Explained by Improvements in Mood Path analysis showed that in addition to improving cognitive function indirectly through the alleviation of depressive symptoms, vortioxetine exerts direct effects on depression-related cognitive impairments as measured by patient performance in relevant tests (DSST). Vortioxetine 5 mg Direct effect DSST Vortioxetine Indirect effect Duloxetine Indirect effect (HAM-D 24) 17% Direct effect (DSST) 83% HAM-D 24 Indirect effect (HAM-D 24) 74% Direct effect (DSST) 26% On RAVLT acquisition, vortioxetine had a 71% direct effect & duloxetine 65% On RAVLT delayed recall, vortioxetine had a 72% direct effect & duloxetine 66% Duloxetine was included as active reference for study validation, not for comparison of effect sizes. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):

22 Examining the Evidence for Direct Impact on Cognitive Symptoms in MDD Antidepressants and psychotropic agents that improve measures of cognition in individuals with MDD independent of improvements in measures of depressive symptom severity Learning/ Memory Attention/ Concentration Executive Function Processing Speed Vortioxetine Duloxetine 1 Lisdexamfetamine 2 Other (eg, SSRIs, SNRIs, and bupropion) Modafinil Erythropoietin Independent effect indicated by a priori specification, cognition as primary; pathoanalysis; subgroup analysis in nonresponders and nonremitters. Level 1 replicated placebo-controlled trial evidence with demonstration of independent effect. Level 2 single placebo-controlled trial evidence with demonstration of independent effect. Level 3 uncontrolled evidence (eg, lacking placebo and case-series) with lack of demonstration of independent effect. McIntyre RS, et al. Curr Opin Psychiatry. 2016;29(1): McIntyre RS, et al. CNS Drugs. 2015;29(7): Points Worthy of Note 1. Pharmacologic treatments can impact cognitive dysfunction, and a growing body of literature is emerging on this topic 2. Receptor pharmacology of various agents appears to have some importance in addressing cognitive dysfunction Take-Home Messages 1. Residual symptoms, including Cognitive Dysfunction, are the rule, and not the exception in MDD 2. All 3 sets of residual symptoms are frequent and they matter Emotional Cognitive Physical 3. Mechanism of action of various antidepressants is important in both its efficacy and side effect profile 4. Fitting the appropriate intervention with the specific patient needs is state-of-the-art practice in 2016