Depression Symptomatology and Neurobiology
Alan J. Gelenberg, MD
Healthcare Technology Systems, Inc, Madison, Wisconsin
Depression is a common condition that is frequently diagnosed and treated by psychiatrists in an outpatient practice and must be distinguished from normal sadness and grieving. Sadness and grief are natural parts of the human emotional heritage in reaction to losses and sad occurrences, whereas depression is a pathological and dysfunctional state that may occur spontaneously or in response to events. In addition to dysfunction or impairment, the DSM-IV-TR1 defines MDD by duration and number of symptoms (AV 1). The DSM-IV-TR distinguishes MDD from dysthymic disorder, which is chronic low-grade depression that often develops into a full major depressive episode during the life of an individual; bipolar disorder, which can periodically include states of depression; and episodes of depression that may result from neurologic or medical conditions.
Depression is considered to be a heterogeneous condition. Biologic abnormalities in the brain may be implicated in problems with sleep, eating, energy, and emotional reactions.2 These abnormalities can affect people's sense of themselves and the world and manifest as depression.
The neurobiology of depression has been of interest since the dawn of the 20th century, and understanding of the neurophysiology and abnormalities that lead to depression is growing. Theories about the pathophysiology of MDD have developed from various sources of information.3 Neuroimaging, for example, has provided evidence regarding brain anatomy and function.4 Advances in brain stimulation technology have contributed to understanding of neuronal networks.5 For illustration, rTMS has shown some efficacy for treatment-resistant depression, but its mechanism of efficacy is not fully understood.6 Response and lack of response to pharmacologic treatments have also provided evidence on the neurobiology of depression.7 Neurogenetics is a promising line of investigation that involves understanding how the human genome affects the brain and how genetic abnormalities (polymorphisms) increase the risk for depression.8
The neuroanatomy of the brain is one focus of theories about the causes of, and treatments for, depression. For instance, the cortex is the part of the brain that allows people to think about and interpret the world around them, while the deeper limbic system is the area of the brain that controls emotion (AV 2).9,10 In individuals with depression, the limbic and cortical regions of the brain have structural abnormalities and neuroimaging has shown abnormalities in brain activity (as indicated by increased cerebral blood flow or decreased glucose metabolism) in many of the same areas.3
Anatomically speaking, depression treatment has targeted the cortex and limbic system. Psychotherapy for depression aims to teach patients to think and interpret differently, thus indirectly influencing their deeper emotional structures "from the top down," as Mayberg stated.4 Conversely, medication presumably affects limbic emotional centers. Patients feel calmer, less threatened, and brighter as they look at themselves and into the future. Their cerebral-cortical area begins to interpret the world in a more benign and hopeful fashion.
Communication between different areas of the brain occurs through neurotransmission, a process in which chemicals flow from 1 neuron to another via neurotransmitters and receptors. In depression, the brain's transmission of monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) presumably is disrupted, and this disruption has been the focus of drug treatment for many years. However, the medications used to treat depression, from the TCAs and MAOIs of the 1950s to the SSRIs and SNRIs of the modern era, probably start a neurobiologic cascade, in which the drugs increase the quantity of monoamine neurotransmitters, probably decrease the sensitivity of receptors, and alter activity in certain neuroanatomic areas.9 As a result of diminished limbic activity and increased prefrontal cortical activity, people become both less anxious and less depressed.7
As researchers begin to understand the genomics of depression, candidate genes, such as the serotonin transporter and certain variations in genetic alleles, have attracted interest because they may cause some individuals to be particularly vulnerable to changes in monoamine neurotransmitter levels in response to psychosocial stressors (AV 3).8 In these individuals, early life experiences of adversity, maltreatment, or abuse and recent adverse life events and perceived lack of social support can increase the risk of depression.8,9,11
"Personalized medicine" is a new focus of research12 that may enable psychiatrists to tailor an intervention to an individual patient's biology. Just as oncologists can design treatments for a specific type of tumor, so psychiatrists may be able to separate depression—which is heterogeneous—into biologically homogeneous conditions that can be treated with unique interventions.
For Clinical Use
- Distinguish depression from normal sadness and grieving by examining the number and duration of symptoms and the impairment they cause
- Recognize that individuals may experience depression symptomatology through various biologic mechanisms and life events and that not all treatments pursue the same biologic targets
APA = American Psychiatric Association, DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MAOI = monoamine oxidase inhibitor, MDD = major depressive disorder, rTMS = repetitive transcranial magnetic stimulation, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant
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- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
- Stahl SM, Zhang L, Damatarca C, et al. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry. 2003;64(suppl 14):6–17.
- Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213(1–2):93–118.
- Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156(5):675–682.
- Rau A, Grossheinrich N, Palm U, et al. Transcranial and deep brain stimulation approaches as treatment for depression. Clin EEG Neurosci. 2007;38(2):105–115.
- Daskalakis ZJ, Levinson AJ, Fitzgerald PB. Repetitive transcranial magnetic stimulation for major depressive disorder: a review. Can J Psychiatry. 2008;53(9):555–566.
- Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48(8):830–843.
- aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ. 2009;180(3):305–313.
- Maletic V, Robinson M, Oakes T, et al. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract. 2007;61(12):2030–2040.
- Stahl MS. Stahl's Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008.
- Nemeroff CB, Vale WW. The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry. 2005;66(suppl 7):5–13.
- National Institutes of Health. From genes to personalized medicines: fact sheet. February 2009. Available at: http://www.nih.gov/about/researchresultsforthepublic/Genes_PersonalizedMed.pdf. Accessed May 1, 2009.