Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Abstract

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine (DA), and possible changes in DA D1 receptors (D1R). It has been appreciated for decades that optimal levels of DA are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted U dose-response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data have, however, spurred efforts towards the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.

An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis

“…The drop-off in LMA at higher doses is typically caused by competition from hyperactivity, with intense stereotyped behaviors such as repetitive grooming (Arnsten et al, 2016) that are incompatible with translational movement. As expected, bell-shaped curves were seen in the hD1 mice with the three D1 agonists, A-77636, SKF 82958, and dihydrexidine (Fig.…”

“…Original research papers (Bruns and Fergus, 1990; Malherbe et al, 2008) and reviews (Christopoulos and Kenakin, 2002; May and Christopoulos, 2003; Epping-Jordan et al, 2007; Arnsten et al, 2016) have emphasized the predicted therapeutic advantages of allosteric potentiators. By amplifying the effectiveness of physiologic circuits, potentiators should give a needed boost to a hypoactive system while allowing the normal feedback loops to remain in control.…”

Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

“…Furthermore, a study of schizotypal personality disorder indicated that the D 1 receptor agonist dihydrexidine improved working memory (Rosell et al, 2015). However, the poor pharmacokinetic characteristics (reviewed by Arnsten et al, 2017) and the known cardiovascular effects of D 1 receptor agonists (e.g. severe hypotension) limit their clinical use.…”

Addressing Cognitive Deficits in Schizophrenia: Toward a Neurobiologically Informed Approach

“…Cognitive deficits are now considered a core feature of schizophrenia; 90% of patients with schizophrenia have deficits in ≥1 cognitive domain, including working memory (WM), attention, processing speed, reasoning and problem solving, social cognition, visual learning and memory, and verbal learning and memory (Table 1) (2,3). In addition, though cognitive symptoms are more predictive of functional outcomes, such as maintaining employment, current pharmacotherapy for schizophrenia focusing on dopamine D 2 receptor antagonism primarily addresses positive (psychotic) symptoms of the illness while leaving cognitive symptoms virtually untouched (2).…”

“…In this issue of Biological Psychiatry , Arnsten et al thoroughly chronicle the research efforts to find a drug that improves cognitive deficits in schizophrenia via the D 1 R (3). Roadblocks have included drugs with poor blood-brain barrier penetration, nonselectivity for D 1 R, partial instead of full agonism, poor oral bioavailability, short duration of action, rapid tolerance, or intolerable side effects.…”