Psychosocial context of antidepressant response

CORRESPONDENCE Psychosocial Context of Antidepressant Response To the Editor: Rush et al (2004) have performed an important public service in evaluating treatment response to antidepressant therapy in depressed public sector patients. The 1-year end point response and remission rates of 26.3% and 14.4%, respectively, were disappointing and were considerably lower than the rates found in other clinical samples (Keitner et al 1992; Ramana et al 1995), including studies limited to chronically depressed subjects (Keller et al 1998). We suggest that a potential explanation for the findings of Rush et al might stem in part from the interaction between the environment and the pharmacologic effects of antidepressants in the brain. Chronic treatment with antidepressants induces a number of cellular effects, including neurogenesis in the hippocampus (Duman et al 2000; Malberg et al 2000). The hippocampus is a critical brain structure for explicit learning and contextual memory. Animal studies suggest that the behavioral benefits of antidepressant medications are mediated through enhanced neurogenesis in the hippocampus (Santarelli et al 2003); however, neurogenesis has to be coupled with new learning and functional connections for the new neurons to survive (Gould et al 1999; Schmidt-Hieber et al 2004). In the absence of such plasticity, the new cells might atrophy and die (Duman et al 2000). Biology does not occur in a vacuum but rather in an environmental context. The public sector population studied by Rush et al presumably experienced significantly greater chronic stress levels (e.g., exposure to violence, financial insecurity, poor physical health, crowding, hunger) than the more affluent populations in the comparison studies. The cellular effects of chronic stress inhibit neurogenesis and counter the effect of antidepressants (Czeh et al 2002). Thus, the stressful environment of the population studied by Rush et al might act to diminish the likelihood of new learning and cell survival, limiting the clinical benefits of antidepressant treatment. This neurobiological perspective is compatible with the social– cognitive learning theory of Bandura (1986), which posits that an individual’s current perceptions are discerned within the context of a cognitive set molded by prior experiences. Only new learning can lead to adaptive changes in this cognitive set. Both the absolute and perceived number of positive life events are likely diminished in public sector patients as compared with more affluent ones. Thus, in many cases of major depression, context trumps pharmacology. Such a conceptualization could explain how employment improved outcome in the study by Rush et al, because employment provided greater potential for new learning and positive experiences. From a public policy standpoint, the findings of Rush et al have profound implications. The resources necessary to deliver effective treatments for major depression in public sector populations necessitate addressing the social environment context. Boadie W. Dunlop Steven J. Garlow Philip T. Ninan Department of Psychiatry and Behavioral Sciences Emory University School of Medicine Wesley Woods Health Center Building 1841 Clifton Road NE, 4th Floor Atlanta, GA 30329 E-mail: [email protected]. 0006-3223/05/$30.00

Bandura A (1986): Social Foundations of Thought and Action: A SocialCognitive Theory. Englewood Cliffs, New Jersey: Prentice-Hall. Czeh B, Welt T, Fischer AK, Erhardt A, Schmitt W, Muller MB, et al (2002): Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: Effects on stress hormone levels and adult hippocampal neurogenesis. Biol Psychiatry 52:1057–1065. Duman RS, Malberg J, Nakagawa S, D’Sa C (2000): Neuronal plasticity and survival in mood disorders. Biol Psychiatry 48:732–739. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999): Learning enhances adult neurogenesis in the adult hippocampal formation. Nat Neurosci 2:260 –265. Keitner GI, Ryan CE, Miller IW, Norman WH (1992): Recovery and major depression: Factors associated with twelve-month outcome. Am J Psychiatry 149:93–99. Keller MB, Gelenberg AJ, Hirschfeld RMA, Rush A, Thase ME, Kocsis JH, et al (1998): The treatment of chronic depression, part 2: A double-blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 59:598 – 607. Malberg J, Eisch A, Nestler E, Duman R (2000): Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20: 9104 –9110. Ramana R, Paykel ES, Cooper Z, Hayhurst H, Saxty M, Surtees PG (1995): Remission and relapse in major depression: A two-year prospective follow-up study. Psychol Med 25:1161–1170. Rush A, Trivedi M, Carmody TJ, Biggs MM, Shores-Wilson K, Ibrahim H, et al (2004): One-year clinical outcomes of depressed public sector outpatients: A benchmark for subsequent studies. Biol Psychiatry 56:46 –53. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al (2003): Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants [see comment]. Science 301:805– 809. Schmidt-Hieber C, Jonas P, Bischofberger J (2004): Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429:184 –187.

doi:10.1016/j.biopsych.2004.11.012

Reply Dunlop and colleagues raise an extremely important issue from both scientific and public policy perspectives. They suggest that environmental stresses might have lead to poorer symptomatic outcomes in patients treated with medication in the absence of psychotherapy in our recent report (Rush et al 2004). Given the chronic, disabling nature of the depressions suffered by these public sector patients and the evidence (Keller et al 2000) that psychotherapy combined with medication resulted in far greater benefits than either therapy or medication alone, such an argument seems reasonable. Other variables, however, could also contribute to the apparently poorer outcome in this patient group, including lower patient adherence to recommended medication and the likely probability of treatment resistance in at least some of these patients. Clearly the best test of Dunlop and colleagues’ interesting idea is a prospective controlled trial in such a group, combining extensive psychosocial and psychotherapeutic interactions with medication, as compared with medication alone. Alternatively, one could compare outcomes with medication alone in two groups defined by differences in day-to-day stress loads. These types of studies would have major public health significance. A. John Rush Department of Psychiatry University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Dallas, TX 75390-9086 E-mail: [email protected] BIOL PSYCHIATRY 2005;57:314 –315 © 2005 Society of Biological Psychiatry