Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia – A path model investigation

Pharmacotherapy of cognitive deficits in schizophrenia

“…The mirtazapine group, in addition to showing an improvement in negative symptoms, demonstrated a statistically significant improvement in vocabulary and immediate memory. In a double-blind trial, Stenberg et al 61 randomized patients with difficult-to-treat schizophrenia to receive either mirtazapine (n 5 19) or placebo (n 5 18) for 6 weeks, and demonstrated improved performance in the mirtazapine group on Block Design and Stroop Dots, which is consistent with mirtazapine having beneficial effects on visuo-spatial functioning. Scoriels et al 62 analyzed results from 9 randomized trials of the pro-dopaminergic agent modafanil in schizophrenia or related conditions, and found that working memory improved with modafanil administration.…”

The Role of Norepinephrine and Its α-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review

“…Reduced filtering of sensory and sensorimotor information, demonstrated by both a reduced P50 suppression or reduced pre-pulse inhibition of the startle reflex, was corrected by activating α 2 -ARs with clonidine (39, 42). Other evidence from our search showed that mirtazapine increased mental speed and attention control in schizophrenia (44), which may be related to its activation of α 2 -ARs.…”

“…A biomarker study showed that elevated NE may be associated with cognitive disorganization, poor impulse control, suspiciousness, hostility, and hallucinations (61). Our findings also suggest that NE manipulation can potentially affect the positive symptoms associated with schizophrenia (43, 44), with the long-term study of adjunctive mirtazapine in patients with schizophrenia showing it improved PANSS positive scores (43), although, this may also be related to modulation of several 5-HT receptors (62). The effectiveness of mirtazapine in schizophrenia is supported by a preclinical study that showed that mirtazapine enhanced the AP activity of haloperidol in an apomorphine-induced climbing test in mice (63).…”

“…Further investigation into factors that may predict and mediate this response revealed that improvements were attributable to increased spatial visualization ability and motor skill as measured by the block design test. Furthermore, pathway analysis indicated that perceived perceptual/cognitive benefits, related to the improvement in attention and processing speed, may be attributable to mirtazapine’s antidepressant properties, rather than direct impact on cognition and negative symptoms of schizophrenia (44). One possible interpretation of these findings is that mirtazapine-associated modulation of α 1 -ARs and α 2 -ARs and consequent “tuning” of NE/5-HT signaling may have played a key role in its ameliorative effect on the positive symptoms of schizophrenia.…”

Protective effects of mirtazapine in mice lacking the Mbnl2 gene in forebrain glutamatergic neurons: Relevance for myotonic dystrophy 1

“…The rationale behind this choice was guided from previous pre-clinical reports showing that chronic treatment with MRZ increases extracellular levels of 5-HT in the frontal cortex of rats (Kamińska et al, 2018), and enhances hippocampal glutamate in both male and female Flinders rats (Kokras et al, 2009), two neurotransmitters that are altered in DM1. In addition, clinical studies show that MRZ modulates proinflammatory markers in patients with depression (Santarelli et al, 2003), which is also a hallmark of DM1 (Stenberg et al, 2013).…”