Depression impairs learning, whereas the selective serotonin reuptake inhibitor, paroxetine, impairs generalization in patients with major depressive disorder

Abstract

To better understand how medication status and task demands affect cognition in Major Depressive Disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the Selective Serotonin Reuptake Inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures critical for generalization.

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

“…Second, whereas vortioxetine selectively increased transcription of multiple genes in the hippocampus, fluoxetine had no effect on the majority of genes assessed. Furthermore, vortioxetine significantly decreased depression-like behavior in 12 month old mice while fluoxetine did not, which is consistent with the clinical observation that elderly patients have a lower response to SSRIs (Tedeschini et al, 2011) and that cognitive deficits in depressed and/ or elderly patients are also relatively insensitive to SSRI treatment (Herzallah et al, 2013). Therefore, our results support that vortioxetine is working via a different mechanism than the SSRI fluoxetine in this model of age-related cognitive deficits.…”

Neurocognitive performance in unmedicated patients with hoarding disorder.

“…However, the majority of prior studies that have addressed neurocognitive functioning in compulsive hoarding reported the inclusion of subjects who were taking prescribed psychotropic medications (Kathmann et al, 2005; Lawrence et al, 2006; Tolin & Villavicencio, 2011; Tolin et al, 2011; Blom et al, 2011; Pinto et al, 2011, Ayers et al, 2013; Morein-Zamir et al, 2013), and the remainder did not report whether subjects were taking medications or list medication use as exclusion criteria. Thus, the neurocognitive deficits in attention, memory, and executive functioning found in those studies might have been due to the effects of psychotropic medications (Amado-Boccara et al, 1995; Wadsworth et al, 2005; Stein & Strickland, 1998; Stewart, 2005; Dias et al, 2012), even those of SRI medications (Tempesta et al, 2013; Herzallah et al, 2013; Lenze et al, 2013) and other antidepressants (Wadsworth et al, 2005). Some prior studies also included subjects who had other comorbid psychiatric disorders known to cause neurocognitive dysfunction, whereas the present study excluded subjects with most of those disorders.…”

“…While the adverse effects of benzodiazepines, mood stabilizers, and antipsychotics on cognitive performance are well known (Amado-Boccara, Gougoulis, Poirier Littre, Galinowski, & Loo, 1995; Wadsworth, Moss, Simpson, & Smith, 2005; Stein & Strickland, 1998; Stewart, 2005; Dias et al, 2012), even serotonin reuptake inhibitor medications and other antidepressants have been associated with impairment in attention, episodic memory, non-verbal memory, and executive function, both in healthy controls (Wadsworth et al, 2005) and in patients with mood and anxiety disorders (Tempesta et al, 2013). The SRI, paroxetine, was found to impair generalization of sequence learning in patients with MDD (Herzallah et al, 2013), while escitalopram has been found to reduce attentional performance in some populations of older adults with GAD (Lenze et al, 2013). Further, cognitive side effects are more prevalent when patients are treated with the higher doses of SRI medications needed for treatment of OCD (Bloch, McGuire, Landeros-Weisenberger, Leckman, & Pittenger, 2010) and related “obsessive-compulsive spectrum disorders” such as HD (Saxena, 2011).…”

Learning and generalization from reward and punishment in opioid addiction

“…The start of a new stage was not signaled to the participant. Because training stages contain different number of trials for each participant, a simple percent error measure is not appropriate, because two participants could have similar numerators but very different denominators; instead, following convention for this type of acquired equivalence task (e.g., 15, 17, 18, 19, 22, 34, 36, 37), we report total errors to criterion on each stage for reward-based and punishment-based antecedents, as well as number of trials to criterion on each stage.…”