Major Depressive Disorder: Understanding the Significance of Residual Symptoms and Balancing Efficacy with Tolerability  Larry Culpepper, MD, MPH, Philip R. Muskin, MD, Stephen M. Stahl, MD  The American Journal of Medicine  Volume 128, Issue 9, Pages S1-S15 (September 2015) DOI: 10.1016/j.amjmed.2015.07.001 Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 1 Symptom dimensions of a major depressive episode.5 In addition to depressed mood and agitation, ≥4 other symptoms are required to make the diagnosis of major depressive disorder. This indicates that there are many types of major depression and that treatment needs to be individualized to the specific symptoms present. From Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013, with permission. The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 2 Proportion of patients with and without residual symptoms: relapse after remission.13 Of patients with residual symptoms, 76% relapsed in 10 months compared with 25% of those without residual symptoms, with permission from Les Laboratoires Servier.15 The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 3 Prevalence of residual symptoms by symptom type in patients with major depressive disorder.19 A higher proportion of patients who do not experience remission have residual symptoms compared with those who achieve remission.33 The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 4 Hypothetical path linking circuits to symptom domains and biomarkers.37 Downstream from inefficient brain circuits are the epigenetic and genetic forces that change gene expression. Both normal and abnormal genes can lead to molecular abnormalities in a circuit or abnormal information processing, which can cause symptoms. Some symptoms can be clustered into diagnostic syndromes, and others may predict treatment response. DSM = Diagnostic and Statistical Manual of Mental Disorders. From Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013. The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 5 Match each diagnostic symptom for a major depressive episode to hypothetically malfunctioning brain circuits.37 The same topographic area or circuit of the brain is responsible for specific symptoms regardless of the psychiatric disorder. For example, sleep and appetite disturbances involve the hypothalamus, and mood disturbances involve another area of the brain. A = Amygdala; BF = Basal forebrain; C = Cerebellum; H = Hippocampus; Hy = Hypothalamus; NA = nucleus accumbens; NT = brainstem neurotransmitter centers; PFC = Prefrontal cortex; S = Striatum; T = Thalamus. From Stahl's Essential Psychopharmacology, 4th ed. 2013, copyright Neuroscience Education Institute, with permission. The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 6 The 5 molecular targets of psychotropic drugs.5,41 Approximately 30% of psychotropic drugs and 90% of antidepressants target the 12-transmembrane region transporter. Another 30% of psychotropic drugs are G-protein linked, and these often are added to antidepressants. Other molecular targets targeted by fewer psychotropic drugs are enzyme inhibitors, which include the monoamine oxidase inhibitors, as well as the 6-transmembrane region voltage gated ion channel and the 4-transmembrane region ligand-gated ion channel transporters. From Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013, with permission. The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 7 Factors explaining antidepressant beliefs.105 Lower adherence to antidepressant medication use is associated with beliefs that are harmful, whereas higher adherence is associated with necessity beliefs. Older patients are more likely to have necessity beliefs, whereas younger patients tend to have harmful beliefs about antidepressant use. Aikens JE, Nease DE Jr, Klinkman MS. Explaining patients' beliefs about the necessity and harmfulness of antidepressants. Ann Fam Med. 2008;6:23-29, with permission from Annals of Family Medicine, Inc. The American Journal of Medicine 2015 128, S1-S15DOI: (10.1016/j.amjmed.2015.07.001) Copyright © 2015 Elsevier Inc. Terms and Conditions