Tachyphylaxis after Repeated Antidepressant Drug Exposure in Patients with Recurrent Major Depressive Disorder
Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-3309, USA. Neuropsychobiology
(Impact Factor: 2.26).
08/2009; 59(4):227-33. DOI: 10.1159/000226611
The aim of this post hoc analysis was to examine whether tachyphylaxis occurs after repeated courses of antidepressant drug therapy.
276 patients with major depressive disorder (MDD) were treated with sertraline (150-200 mg daily) for 8 weeks. Patients with persistent MDD after sertraline therapy were randomized to continuation therapy with either sertraline plus atomoxetine (n = 72) or sertraline plus placebo (n = 74) for 8 additional weeks. Logistic regression was used to test the hypothesis that an increase in prior antidepressant drug exposure is associated with a reduced responsiveness to sertraline therapy.
The number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy (odds ratio = 0.81, p = 0.0035). The odds ratio indicates a 19.9% reduced likelihood of response with each prior antidepressant treatment trial. In contrast, the number of prior antidepressant treatment trials was not associated with response to continuation sertraline plus atomoxetine or sertraline plus placebo therapy.
This observation supports the hypothesis that tachyphylaxis may develop after repeated antidepressant drug trials.
Available from: Paul W. Andrews
- "With so many possible pathways to MDD, repeated episodes in a single patient may not have the same cause. We noted earlier that antidepressant medications can sometimes lose efficacy over time (Amsterdam et al., 2009; El-Mallakh et al., 2011 "
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ABSTRACT: Major depressive disorder (MDD) presents with a variety of symptoms and responds to a wide range of treatment interventions. Diagnostic criteria collapse multiple syndromes with distinct etiologies into the same disorder. MDD is typically understood as a malfunction of neurotransmission or brain circuitry regulating mood, pleasure and reward, or executive function. However, research from an evolutionary perspective suggests that the “normal” functioning of adaptations may also generate symptoms meeting diagnostic criteria. Functioning adaptations may be an underappreciated etiological pathway to MDD. Many adaptive functions for depressive symptoms have been suggested: biasing cognition to avoid losses, conserving energy, disengaging from unobtainable goals, signaling submission, soliciting resources, and promoting analytical thinking. We review the potential role of these adaptive functions and how they can lead to specific clusters of depressive symptoms. Understanding MDD from such a perspective reduces the heterogeneity of cases and may help to select the best intervention for each patient. We discuss the implications of different adaptive and maladaptive etiological pathways for the use of antidepressants and various modes of psychotherapy. In particular, instances of MDD caused by functioning adaptations may benefit most from treatments that support the adaptive function, or that target the precipitating causal stressor. We conclude that an evolutionary approach to the study of MDD may be one of the more promising approaches to reduce its heterogeneity and to better match patients and treatment.
Available from: Andrew F Leuchter
- "Sustained or repeated exposure to a drug can elicit different forms of conditioning including compensatory physiologic responses resulting in tolerance . In the context of antidepressant treatment, a clinical literature suggests that the clinical efficacy of antidepressant treatment may decrease over prolonged or repeated administrations , such as in 'tachyphylaxis'     . "
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ABSTRACT: Major Depressive Disorder (MDD) is a lifelong and recurrent illness, such that many individuals require multiple courses of antidepressant medication treatment. While some patients respond completely to each course of treatment, many do not, and with each unsuccessful antidepressant trial the likelihood that a patient will respond decreases. This raises the possibility that neurophysiologic response in subsequent antidepressant treatment may be influenced by learning processes including sensitization, habituation, and/or classical conditioning. Classical conditioning would entail the association of cues such as pill-taking (conditioned stimuli; CS) with the effects of active medication (unconditioned stimulus; US), such that later presentation of the CS alone would come to elicit a conditioned response (CR). Such effects could be revealed by blinded administration of placebo following a period of treatment with active medication. Habituation effects (tolerance), or sensitization effects (increased response), which require only repeated exposure to a stimulus, might be evidenced after repeated courses of antidepressant treatment. Knowledge of how learning processes impact neurophysiologic response to successive courses of antidepressant treatment would have relevance for clinical populations. Specific hypotheses, however, may be tested in healthy non-clinical samples to avoid potential confounding factors related to severity or chronicity of illness. Learning theories would suggest two hypotheses: (1) neurophysiologic response to placebo will differ between subjects who were previously treated with antidepressant treatment as compared to placebo (classical conditioning hypothesis); and (2) neurophysiologic response to an initial course of antidepressant treatment will differ from response to a repeated course of antidepressant treatment. Pilot data addressed these hypotheses in healthy never-depressed women who had previously received four weeks of venlafaxine IR, 150mg (antidepressant-experienced subjects; n=2) or matching placebo (antidepressant-naive subjects; n=4) under double-blind conditions. Six-and-a-half years later, we treated these six women with placebo for one week, followed by four weeks of double-blind treatment with venlafaxine IR, 150mg. Brain functional changes over the course of treatment were assessed using quantitative electroencephalography (qEEG) to compare prefrontal neurophysiologic responses between subjects who had, versus had not, previously been exposed to venlafaxine. Antidepressant-experienced versus antidepressant-naive subjects showed greater decreases in prefrontal cordance (PFC) during venlafaxine administration (sensitization hypothesis) but did not show significantly different PFC changes during treatment with placebo in this small pilot sample (classical conditioning hypothesis). Data suggest that brief treatment with antidepressant medication may have an enduring impact on neurophysiologic responses to a subsequent course of antidepressant treatment. Hypotheses should be tested in larger samples.
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ABSTRACT: The effectiveness of electroconvulsive therapy (ECT) in pharmacotherapy-resistant major depressive disorder and schizophrenia has been shown for all age groups. Nevertheless, age-specific adverse effects such as greater cognitive impairment and higher somatic risks due to medical comorbidities and concomitant medication may be limiting factors in geriatric patients.
We retrospectively evaluated 4457 treatments in 380 patients to investigate the influence of age on ECT outcome, safety, and adverse effects. Clinical variables, treatment modalities, and neurophysiological parameters were analyzed. For modeling the influence of age on these variables of interest, linear and logistic regression models were performed.
The mean (SD) age of our patients was 51.2 (15) years; 30% were older than 60 years. Diagnoses were major depressive disorder in 74.4% and schizophrenia in 25.6%. We found a considerable clinical improvement in all age groups. A higher severity of disease at admission corresponded to a better clinical response. Analyzing treatment modalities of elderly patients older than 60 years, no significant differences in need and number of concomitant psychotropic medications were seen, but significant differences were seen in medical co-medication. Ictal and postictal neurophysiological parameters were only in part predictive for clinical outcome, but age had a significant influence on most of them. Transient cardiovascular adverse effects and cognitive disturbances were more frequent in the elderly. In most cases, there was no need for any specific treatment.
Our data confirm previous studies indicating the good effectiveness of ECT irrespective of age. We also found an excellent tolerability profile in the elderly in our patient sample. There was no mortality, and only transient and no life-threatening adverse events occurred.
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