Another meta-analysis of existing studies in which patients were discontinued from antidepressants and found to "relapse" -- except that this paper admits "discontinuation studies vary widely in the criteria that are used to define a relapse.....Prior meta-analyses have not attempted to control for the variability in the stringency of relapse criteria in discontinuation studies, possibly because it is difficult to objectively compare relapses defined by different instruments."
This paper supports Giovanni Fava's theory of oppositional tolerance -- that the brain compensates for the action of antidepressants and attempts to recover normal equilibrium among neurotransmitters. While G. Fava et al 2010 and El-Mallakh et al 2011 suggest antidepressants overpower the brain's natural inclination to homeostasis, Andrews et al take the view of evolutionary psychiatry: The brain adapts and re-adapts, maintaining homeostasis as it was intended to do.
In this paper, the disruption of normal functioning by antidepressants is called "perturbational effects."
Unusually readable for a scientific paper, it is more than 50 pages long.
Front. Psychology 2:159. 2011 June.
Blue again: Perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression
Paul Andrews, Susan Kornstein, Lisa Halberstadt, Charles Gardner and Michael C. Neale
Abstract at http://www.frontiers....00159/abstract Free full text here.
Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.
-------SELECTIONS FROM THE PAPER--------
Table 1. Perturbational effects of antidepressants on mPFC levels of monoamine neurotransmitters (expressed as percent over baseline).
11_0623_blue_again_table1.png 49.91KB 1 downloads
[The paper goes into a concise and readable overview of what types of antidepressants bind to what receptors and to what degree.]
To summarize, we conduct a meta-analysis to test two predictions of the hypothesis that monoamine levels are under homeostatic control in patients diagnosed with MDD. First, patients who remit with ADM treatment will have a higher risk of relapse after treatment stops than patients who remit without ADM treatment. Second, the risk of relapse after ADM treatment is discontinued will be positively related to the perturbational effects of the ADM on prefrontal monoamine levels....
Two types of studies are relevant to these predictions. In ADM extension studies, patients diagnosed with MDD are initially randomly assigned to ADM or placebo during the treatment phase, and then remitters in both groups are followed in an extension phase in which they continue to receive the same treatment. Since our first prediction relates to the risk of relapse after remission without ADM treatment, we only consider the Placebo-Placebo arms of extension studies. We put placebo in its own class (PBO) and assign to placebo treatment a perturbational score of 100 (no effect on baseline levels) for each of the monoamines.
In ADM discontinuation studies, all patients diagnosed with MDD go through an initial ADM treatment phase and then remitters go through a discontinuation phase in which they are randomly assigned, under double-blind conditions, to either continued treatment (Drug-Drug) or placebo (Drug-Placebo). Since our second prediction deals with the risk of relapse after ADM discontinuation, we only consider the Drug-Placebo arms of discontinuation studies....
[The study identified these factors that could affect the reported relapse rate:
Demographic variables (age, sex)
Depression history (dephx)
Treatment resistance (txresist)
Drug variables (class, halflife)
Treatment duration (txdur)
Dropout rate during Treatment (droprate)
Relapse risk period (riskper)
Stringency of criteria for defining depressive relapse (stringency)
Relapse rate (relrate)]
We do not distinguish between patients who experienced a recurrence (onset of a new episode) from those who relapsed back into their index episode. For consistency, we refer to all lapses of remission as relapses, though some may be recurrences....
Forty six papers met inclusion criteria, constituting 49 samples and 3,454 patients....
We found robust support for our predictions. The risk of relapse after ADM discontinuation was higher than the risk of relapse after remission on placebo. Moreover, the risk of relapse was after ADM discontinuation was positively predicted by the degree to which ADMs perturbed 5-HT and NE levels in the rodent mPFC. The risk of relapse was also positively predicted by the degree to which ADMs perturbed DA levels in the mPFC. Given the high degree of collinearity between the perturbational effects of ADMs on NE and DA, we prefer the 5-HT/NE model over the 5-HT/DA model because the evidence for the involvement of NE in depression is stronger.
While the results are robust, their implications depend on their interpretation, so we first discuss several potential confounds. Is it possible, for instance, that the results do not reflect the risk of relapse, but rather withdrawal symptoms? The discontinuation of antidepressant medication can cause withdrawal symptoms (also known as discontinuation syndrome) that are unrelated to relapse, but may sometimes be mistaken for relapse (Haddad, 1997). Such mistakes are more likely with untrained physicians (Haddad, 1997), so it should be less of a problem in ADM discontinuation studies where trained psychiatrists are employed to evaluate putative cases of relapse. Regardless, drugs with longer half-lives are less likely to show discontinuation syndrome (Fava, 2006; Michelson et al., 2000). If discontinuation syndrome were being mistaken for relapse, then drugs with longer half-lives should have lower relapse rates. To test this possibility, we added half-life to the best-fitting model and eliminated the perturbational variables (results not shown). The resultant model did not fit as well, and, in fact, half-life was a significant positive predictor of relapse rate. This is because drugs with stronger perturbational effects on 5-HT tend to have longer half-lives. We therefore have no evidence that withdrawal symptoms were mislabeled as relapses.
There is some evidence that ADM treatment resistant patients may have higher relapse rates (Rush et al., 2006). Is it possible that studies using ADMs with stronger perturbational properties had higher relapse rates, not due to the pharmacological properties of the drugs used, but because they also had higher proportions of treatment resistant patients participating in them? There are two ways this could happen. First, studies using stronger ADMs could have been more likely to target treatment resistant patients at the outset. Second, the characteristics of patient samples in discontinuation studies may change during treatment due to dropouts caused by the treatment, causing a potential selection bias problem.
A related issue is whether the PBO class (denoted by the Placebo-Placebo arms of the extension studies) was fundamentally different from the other classes (denoted by the Drug- Placebo arms of the ADM discontinuation studies). For instance, perhaps the PBO studies targeted fundamentally different samples at the outset, or perhaps they had higher dropout during the acute treatment phase so that patient populations were substantially different by the beginning of the extension phase. Consistent with this, the PBO studies did have a higher dropout rate and a lower relapse rate than the ADMs as a group. Of course, this result might also be expected if the PBO studies were quantitatively different only because they were on one end of the perturbational continuum....
Our results support the conclusion that prolonged ADM use triggers oppositional tolerance in patients meeting diagnostic criteria for MDD. As predicted by an oppositional tolerance model, the risk of relapse was higher after ADM discontinuation than the unmedicated risk of relapse. Also, the risk of relapse after ADM discontinuation was proportional to the perturbational effect of the ADM on rodent mPFC. This result is analogous to the oppositional force produced by a spring, which is proportional to the deviation from the equilibrium position. Our results therefore provide no evidence of malfunction in either the sensor or feedback components of monoaminergic homeostatic mechanisms in patients with episodes that satisfy current criteria for MDD....
In short, we found no positive evidence to support, and some positive evidence to contradict, the claim that most patients diagnosed with MDD have a monoaminergic disorder. Nor is there any evidence that the current diagnostic reliance on distress and impairment accurately identifies depressive disorder....
It is commonly thought that ADM treatment should continue until the index episode resolves, else relapse will recur. For this reason, maintenance ADM therapy is often recommended for 4-12 months or more after the acute management of the index episode (Geddes et al., 2003). Nevertheless, there are troubling empirical problems with these guidelines. For instance, in naturalistic studies, unmedicated patients have much shorter episodes, and better long-term prospects, than medicated patients (Coryell et al., 1995; Goldberg, Privett, Ustun, Simon, & Linden, 1998; Posternak et al., 2006). Several of these studies have found that the average duration of an untreated episode of major depression is 12-13 weeks (Coryell et al., 1995; Posternak et al., 2006). Since acute ADM management of major depression minimally requires several weeks to reduce symptoms, the duration of untreated episodes is much shorter than the recommended duration of ADM therapy. This suggests that ADM therapy may delay resolution of depressive episodes.
Current maintenance therapy guidelines are based primarily on prior meta-analyses that have found that the relapse rates in the Drug-Drug arms of ADM discontinuation studies are consistently lower than in the Drug-Placebo arms (Geddes et al., 2003; Glue et al., 2010; Kaymaz et al., 2008; Viguera et al., 1998). This is often interpreted as evidence that ADM therapy prevents depressive relapse. However, our results suggest that oppositional tolerance to the ADM contributes to the high risk of relapse in the Drug-Placebo arms of these studies, which undermines the rationale for maintenance therapy. Moreover, if continuous ADM therapy were needed until the index episode resolved, then ADM discontinuation studies with longer periods of continuous treatment should have lower relapse rates. This prediction has not been supported in any prior meta-analysis of ADM discontinuation studies. We also did not find treatment duration to have a protective effect on the risk of relapse. Rather, we found a non-significant trend for longer periods of continuous ADM treatment to be associated with a greater risk of relapse. Maintenance therapy guidelines should be re-examined....
Dependency on ADMs
Drugs that promote the risk of relapse or withdrawal upon discontinuation can cause dependence on the drug to prevent the return of symptoms (Chouinard, 2004). Consequently, such drugs must be managed carefully and patients must provide informed consent for their use (Bursztajn & Brodsky, 1998). ADMs are sometimes prescribed to people with alcohol or illicit drug dependencies (Petrakis, Leslie, & Rosenheck, 2003), because the use of such substances to medicate feelings of anxiety and depression is thought to play a role in the dependency (Tomlinson, Tate, Anderson, McCarthy, & Brown, 2006). Ironically, the use of ADMs to help people wean off such substances might merely replace one dependency with another.
Treating depression with multiple psychotropic drugs
Since many patients on antidepressants alone do not achieve full remission (Rush et al., 2006), possibly due to oppositional tolerance, atypical antipsychotic drugs and other agents are increasingly prescribed to enhance the efficacy of ADMs. Our results suggest that the concurrent use of multiple drugs could cause greater monoaminergic perturbations, possibly further increasing the risk of relapse after they are discontinued.
Edited by Altostrata, 20 August 2016 - 08:27 AM.