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Review
. 2019 Apr 30:13:404.
doi: 10.3389/fnins.2019.00404. eCollection 2019.

Overcoming Resistance to Selective Serotonin Reuptake Inhibitors: Targeting Serotonin, Serotonin-1A Receptors and Adult Neuroplasticity

Faranak Vahid-Ansari  1 , Min Zhang  1 , Amin Zahrai  1 , Paul R Albert  1
Affiliations
Review

Overcoming Resistance to Selective Serotonin Reuptake Inhibitors: Targeting Serotonin, Serotonin-1A Receptors and Adult Neuroplasticity

Faranak Vahid-Ansari et al. Front Neurosci. .

Abstract

Major depressive disorder (MDD) is the most prevalent mental illness contributing to global disease burden. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are the first-line treatment for MDD, but are only fully effective in 30% of patients and require weeks before improvement may be seen. About 30% of SSRI-resistant patients may respond to augmentation or switching to another antidepressant, often selected by trial and error. Hence a better understanding of the causes of SSRI resistance is needed to provide models for optimizing treatment. Since SSRIs enhance 5-HT, in this review we discuss new findings on the circuitry, development and function of the 5-HT system in modulating behavior, and on how 5-HT neuronal activity is regulated. We focus on the 5-HT1A autoreceptor, which controls 5-HT activity, and the 5-HT1A heteroreceptor that mediates 5-HT actions. A series of mice models now implicate increased levels of 5-HT1A autoreceptors in SSRI resistance, and the requirement of hippocampal 5-HT1A heteroreceptor for neurogenic and behavioral response to SSRIs. We also present clinical data that show promise for identifying biomarkers of 5-HT activity, 5-HT1A regulation and regional changes in brain activity in MDD patients that may provide biomarkers for tailored interventions to overcome or bypass resistance to SSRI treatment. We identify a series of potential strategies including inhibiting 5-HT auto-inhibition, stimulating 5-HT1A heteroreceptors, other monoamine systems, or cortical stimulation to overcome SSRI resistance.

Keywords: antidepressant; autoreceptor; brain stimulation; brain-derived growth factor; imaging; knockout; noradrenalin; serotonin.

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Figures

FIGURE 1
FIGURE 1
Summary of target sites to overcome SSRI resistance. Shown is a 5-HT neuron (yellow) that is refractory to SSRI treatment. Brain regions highlighted include raphe containing 5-HT neurons, locus coeruleus containing norepinephrine (NE) neurons (orange), and forebrain (green), which includes frontal cortex, hippocampus, amygdala, brain regions implicated in antidepressant response. Several potential sites of intervention to augment SSRI response or bypass SSRI treatment are shown. These include: (1) Blocking (X) auto-inhibition (via 5-HT1A autoreceptor or signaling blockers); (2) Reducing 5-HT1A autoreceptor expression (via desensitization, HTR1A gene repression or 5-HT-targeted 5-HT1A siRNA); (3) Increasing (arrow) 5-HT neuronal activity (via cortical stimulation); (4) Increasing 5-HT neuroplasticity (e.g., synaptogenesis); (5) Increasing 5-HT1A heteroreceptor activity (via biased 5-HT1A agonists); (6) Increasing 5-HT1A heteroreceptor expression (via inhibiting 5-HT1A-selective repressor activity); (7) Increasing cortical activity (via ketamine, cortical stimulation); (8) Bypassing 5-HT (via activation of other monoamines such as NE using transporter blockers or agonists).
FIGURE 2
FIGURE 2
Opposite roles of 5-HT1A autoreceptor vs. heteroreceptors in behavior and SSRI response. Shown are the effects on the serotonin system and behavior in mouse or rat knockout/knockdown (X) genetic models compared to wild-type animals. Models included were generated with: (A) Over-expression of 5-HT1A autoreceptors (using knockout of 5-HT1A repressor Freud-1/CC2D1A in adult 5-HT neurons); (B) knock-down of 5-HT1A autoreceptors (using raphe-targeted 5-HT1A siRNA (Bortolozzi et al., 2012) or inducible genetic knock-down); or (C) loss (using gene knockout) of 5-HT1A heteroreceptors in hippocampal granule cells. The effect of these knockouts on 5-HT1A transcription (right angle arrow) and receptor levels, 5-HT auto-inhibition (curved red arrows), 5-HT neuronal activity (black arrows), depression- or anxiety-like behavior and response to chronic SSRI treatment (++, + or -) are shown. Increasing the expression of 5-HT1A autoreceptors reduces 5-HT activity leading to anxiety and/or depression-like behavior resistant to SSRI treatment (Vahid-Ansari et al., 2017). Knockdown of adult 5-HT1A autoreceptors induces a stress-resilient state and enhances SSRI responsiveness (++) (Richardson-Jones et al., 2010), but can also lead to an anxiogenic response to subchronic SSRI with extensive knockdown (Turcotte-Cardin et al., 2019). The loss of hippocampal granule cell 5-HT1A heteroreceptors leads to depression and anxiety phenotypes and prevents SSRI response (Samuels et al., 2015).
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