Increased Lower Limb Spasticity but Not Strength or Function Following a Single-Dose Serotonin Reuptake Inhibitor in Chronic Stroke

Objective: To investigate the effects of single doses of a selective serotonin reuptake inhibitor (SSRI) on lower limb voluntary and reflex function in individuals with chronic stroke. Design: Double-blind, randomized, placebo-controlled crossover trial. Setting: Outpatient research setting. Participants: Individuals (N=10; 7 men; mean age ± SD, 57±10y) with poststroke hemiplegia of \u3e1 year duration who completed all assessments. Interventions: Patients were assessed before and 5 hours after single-dose, overencapsulated 10-mg doses of escitalopram (SSRI) or placebo, with 1 week between conditions. Main Outcome Measures: Primary assessments included maximal ankle and knee isometric strength, and velocity-dependent (30°/s–120°/s) plantarflexor stretch reflexes under passive conditions, and separately during and after 3 superimposed maximal volitional drive to simulate conditions of increased serotonin release. Secondary measures included clinical measures of lower limb coordination and locomotion. Results: SSRI administration significantly increased stretch reflex torques at higher stretch velocities (eg, 90°/s; P=.03), with reflexes at lower velocities enhanced by superimposed voluntary drive (P=.02). No significant improvements were seen in volitional peak torques or in clinical measures of lower limb function (lowest P=.10). Conclusions: Increases in spasticity but not strength or lower limb function were observed with single-dose SSRI administration in individuals with chronic stroke. Further studies should evaluate whether repeated dosing of SSRIs, or as combined with specific interventions, is required to elicit significant benefit of these agents on lower limb function poststroke

Voluntary activation of muscle in humans: Does serotonergic neuromodulation matter?

Ionotropic inputs to motoneurones have the capacity to depolarise and hyperpolarise the motoneurone, whereas neuromodulatory inputs control the state of excitability of the motoneurone. Intracellular recordings of motoneurones from in vitro and in situ animal preparations have provided extraordinary insight into the mechanisms that underpin how neuromodulators regulate neuronal excitability. However, far fewer studies have attempted to translate the findings from cellular and molecular studies into a human model. In this review, we focus on the role that serotonin (5-HT) plays in muscle activation in humans. 5-HT is a potent regulator of neuronal firing rates, which can influence the force that can be generated by muscles during voluntary contractions. We firstly outline structural and functional characteristics of the serotonergic system, and then describe how motoneurone discharge can be facilitated and suppressed depending on the 5-HT receptor subtype that is activated. We then provide a narrative on how 5-HT effects can influence voluntary activation during muscle contractions in humans, and detail how 5-HT may be a mediator of exercise-induced fatigue that arises from the central nervous system. (Figure presented.)

One‐week escitalopram intake alters the excitation–inhibition balance in the healthy female brain

Neural health relies on cortical excitation-inhibition balance (EIB). Previous research suggests a link between increased cortical excitation and neuroplasticity induced by selective serotonin reuptake inhibitors (SSRIs). Whether there are modulations of EIB following SSRI-administration in the healthy human brain, however, remains unclear. Thus, in a randomized double-blind study, we administered a clinically relevant dose of 20 mg escitalopram for 7 days (time when steady state is achieved) in 59 healthy women (28 escitalopram, 31 placebo) on oral contraceptives. We acquired resting-state electroencephalography data at baseline, after a single dose, and at steady state. We assessed 1/f slope of the power spectrum as a marker of EIB, compared individual trajectories of 1/f slope changes contrasting single dose and 1-week drug intake, and tested the relationship of escitalopram plasma levels and cortical excitatory and inhibitory balance shifts. Escitalopram-intake was associated with decreased 1/f slope, indicating an EIB shift in favor of excitation. Furthermore, 1/f slope at baseline and after a single dose of escitalopram was associated with 1/f slope at steady state. Higher plasma escitalopram levels at a single dose were associated with better maintenance of these EIB changes throughout the drug administration week. These findings demonstrate the potential for 1/f slope to predict individual cortical responsivity to SSRIs and widen the lens through which we map the human brain by testing an interventional psychopharmacological design in a clearly defined endocrinological state

Psychiatric medication and physical performance parameters – are there implications for treatment?

Introduction The impact of psychiatric medications and their enhancing or impairing effects on physical performance remains inconclusive. Therefore, with this systematic review we provide a comprehensive overview of frequently used psychotropic drugs and their effects on physical performance for the purpose of providing empirical information and deriving prescription and therapy recommendations for clinical practice. Methods We systematically searched PubMed, PsycInfo, and Cochrane databases and extracted human studies investigating the effect of psychotropic drugs on parameters associated with the level of physical performance, such as exercise time, oxygen consumption, heart rate, muscle contraction or blood lactate concentration in physically healthy participants. 36 studies - comprising a broad range of psychotropic agents, such as antidepressants, antipsychotics, sedatives, and stimulants - were selected for final analyses. Results Most studies (N = 32) were randomized controlled trials (RCT) with a double-blind crossover design. Antidepressants (N = 21) were the most frequently studied drug class, with contradictory results e.g., performance enhancement in warm environment but not in temperate conditions for bupropion or inconsistent findings between studies for other antidepressants. Antipsychotics (N = 3) mainly showed impairing effects on physical performance, while stimulants (N = 4) were often performance-enhancing. Sedatives (N = 9) may cause a hangover effect. Conclusion The examined studies with heterogeneous design showed different effects of psychiatric medications on physical performance. Antipsychotics seemed to be performance impairing, while the findings for antidepressants and sedatives were more inconsistent. Stimulants were the only group with consistent performance-enhancing effects. However, most studies were conducted with a small sample size (N < 10), mostly in well-trained subjects rather than in patients with psychiatric disorders, and most studies used single-dose designs. These issues impede the formulation of generalized conclusions for treatment regimes and should therefore be considered in further longitudinal studies for clinically reliable statements. Nevertheless, answering our research question is quite relevant for clinical practice and therapeutic prescription and should be further investigated especially considering the high drop-out rates in drug treatment. Systematic review registration [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=276103], identifier [CRD42021276103]

Effects of chronic paroxetine and fluoxetine treatment on markers of suicidal behavior in adolescent rats

Major depression is a common problem in adolescents. Unfortunately, one of the most effective antidepressants in adults, the selective serotonin reuptake inhibitor (SSRI) paroxetine, is not clinically effective in pediatric populations. There are many variables that increase the risk of suicide including genetic, social, psychological, and biological factors, making the evaluation of the effect of SSRIs on suicidal behavior difficult to assess in human adolescents. The goal of the present investigation was to compare the effects of paroxetine and fluoxetine in adolescent rats on markers associated with depression and suicidal behavior in humans

A Critical Window? Longitudinal Changes in Plasticity in Motor Cortex following Ischaemic Stroke

While spontaneous recovery occurs in most patients following stroke, it is often incomplete. Recovery seems to be mostly confined to the first 6 months. Data from animal models suggest there is a critical period of enhanced plasticity similar to that seen in early development. Evidence for such a critical period has not yet been established in humans. Repetitive transcranial magnetic stimulation is a suitable tool for measuring changes in plasticity in human motor cortex. However, its long-term test-retest reliability has not been widely studied. Experiment 1 19 younger (average 29.9 years) and 20 older (average 65.9 years) subjects had repeat sessions of spaced cTBS to motor cortex 6 months apart. Change in average MEPs over 30 minutes post spaced cTBS showed fair intraclass correlation across 6 months in young (0.458 CI [-0.406, 0.791]) and older (0.572 [95%CI -0.08, 0.83]) subjects. This is broadly equivalent to other forms of plasticity-modulating non-invasive brain stimulation. Experiment 2 29 subjects (average 68.2 years) had repeat spaced cTBS to contralesional motor cortex at 2, 4, 6 and 26 weeks following ischaemic stroke. There was a significant decrease in LTDlike plasticity across sessions (p<0.01). There was no change in resting motor threshold in either hemisphere and no change in intracortical excitability. Small vessel disease measured on MRI did not influence response to spaced cTBS. Experiment 3 To complement the expansion in clinical research examining the benefits of fluoxetine in enhancing post-stroke plasticity, 31 healthy volunteers (average age 26.3 years) received fluoxetine 20mg or placebo prior to undergoing spaced cTBS in a double-blind randomised cross-over trial. There was no effect of fluoxetine on response to cTBS (p=0.472). Conclusions There is a decrease in LTD-like plasticity in the 6 months following a stroke in humans. 20mg of fluoxetine had no effect on LTD-like plasticity in healthy subjects

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe