Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review. (2015)

Hopefully the following provides some direction for treating the cognitive deficits associated with schizophrenia…

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review. (2015)

Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant’s action, whose potential effectiveness was assessed in randomized placebo-controlled trials (RCTs). A systematic review was carried out, using the words “attention”, “memory”, “learning”, “executive functions”, and “vigilance/wakefulness” combined to “cognitive enhancer” or “smart drug”. Methylphenidate, amphetamines, modafinil, nicotine, acetylcholine esterase inhibitors and antidepressants were extensively studied in previous meta-analyses and were not included in the present work. Drugs were classified according to their primary mode of action, namely catecholaminergic drugs (tolcapone, pramipexole, guanfacine), cholinergic drugs (anticholinergics), glutamatergic drugs (ampakines), histaminergic drugs, and non-specified (glucocorticoids). Overall, 50 RCTs were included in the present review. In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However the number of RCTs was limited, and most of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). One explanation for the limited number of recent RCTs with new psychostimulants seems to be the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

table 1Some findings mentioned in the article:

  • Tolcapone (200 mg single dose) is known to significantly improve executive function and verbal episodic memory performance in healthy adults (Apud et al., 2007 and Roussos et al., 2009). Tolcapone 100 mg three time a day for 1 day and 200 mg three times a day for 6 days showed no performance variation during a non conventional attentional control task (Magalona et al., 2013).
  • A 0.5 mg single dose of pramipexole has been found to induce sleepiness in healthy subjects (Micallef et al., 2009) and to impair reinforcement learning (Pizzagalli et al., 2008).
  • Guanfacine and clonidine both increased visual learning (Jakala et al., 1999). In another trial, clonidine administration (150–300 µg) was associated with subjective sedation and impaired performance (especially in attention) in 15 young adults (Tiplady et al., 2005). Clonidine impaired working memory while inducing feelings of drunkenness, but did not alter long-term formation of memories. Another study found no effect of guanfacine on executive functions and working memory in a population of healthy male adults (Muller et al., 2005). Guanfacine has also been found to influence emotional memory via modulation of the prefrontal cortex (Schulz et al., 2013).
  • Biperiden has been found to enhance episodic memory performance in healthy elderly subjects in one RCT (Wezenberg et al., 2005). Another trial found that 1–2 mg trihexyphenidyl improved verbal memory in 24 healthy elderly (Pomara et al., 2010). However, in a third trial, biperiden (4 mg) and trihexyphenidyl (5 mg) were both found to decrease memory performance (Guthrie et al., 2000)
  • Farampator (500 mg single dose) improved short-term memory, but appeared also to impair episodic memory in 16 healthy elderly volunteers (Wezenberg et al., 2007).
  • CX-516 (1-(quinoxalin-6 ylcarbonyl)piperidine) (300–900 mg, single dose) was found to improve short-term delayed memory in three RCTs (respectively 24 and 50 healthy young individuals and 18 elderly individuals (Ingvar et al., 1997, Lynch et al., 1997 and Lynch et al., 1996).
  • A single dose of 3 mg melatonin specifically enhanced recognition memory accuracy of objects encoded under stress in 27 young volunteers versus 23 placebo controls (Rimmele et al., 2009).
  • “Human studies investigating the effects of acute GC treatment on memory have reported conflicting (enhancing as well as impairing) results. A meta-analysis of 16 studies (N=563 healthy volunteers, mean age 24.23 years (SD+/−2.15)), which experimentally investigated the acute impact of cortisol treatment (hydrocortisone) on human memory, revealed that the timing of GC application in the course of a study is a relevant variable, which explains a substantial amount of the significant heterogeneity within the effect sizes ( Het et al., 2005). The used doses of hydrocortisone ranged from 5 to 100 mg (median=25 mg; DM+/−7.5). Retention interval ranged from 0 (immediate recall) up to 168 h (delayed recall). Four studies, which administered cortisol before retrieval, reported a significant decrease (average effect size of d=−0.49) in memory performance. Twelve studies, which administered cortisol before learning, found on average no effect (d=0.08), but there was heterogeneity within these effect sizes. Further analysis on these experiments indicated that studies administering cortisol in the morning found a significant memory impairment (d=−0.40), while studies conducted in the afternoon observed a small but significant memory enhancement (d=0.22) ( Het et al., 2005).”
  • A recent RCT showed that 10 mg single-dose hydrocortisone administration 45 min prior to the testing was associated with an enhancing effect on inhibitory performance in 54 healthy volunteers (Schlosser et al., 2013), a working memory impairment in another sample of 56 healthy volunteers (Terfehr et al., 2011) and to fewer specific memories on the autobiographical memory testing ( Schlosser et al., 2010). Some positive effects of 10 mg hydrocortisone on selective attention were also reported (Henckens et al., 2012)
  • Aspirin pre-treatment (600 mg, single dose) was found to improve working memory in healthy adults (Watson et al., 2009).


“Some potential cognitive enhancers with innovative mechanisms of action have not been tested in healthy subjects to date. GABAα5 blockers may provide a nootropic effect without the associated anxiogenic effects of general GABA inverse agonism (Koh et al., 2013 and Milic et al., 2013). Sigma agonists receptors increase acetylcholine release in both the hippocampus and the frontal cortex in rodent models (Matsuno et al., 1995) and may potentiate several NMDA-evoked responses in selected regions of the hippocampus (Hong and Werling, 2000). Piracetam and piracetam-like molecules are thought to be neuroprotective agents with potential enhancement properties, possibly due to their common 2-oxopyrrolidine structure (Gualtieri et al., 2002). Ampakine activity has been established as one of the modes of action of the racetams. However, these drugs have multiple modes of action and produce only weak AMPA receptor activation and it is unclear how significant their ampakine actions are in producing their positive effects. Animal studies suggest memory and wakefulness enhancement properties of several racetams (Barad et al., 1998, Grossman et al., 2011, Lelkes et al., 1998, Mondadori et al., 1986, Samartgis et al., 2012, Scheuer et al., 1999, Trofimov et al., 2005 and Tushmalova et al., 1995). It is noteworthy that animal experiments focused on restoring age-impaired cognitive functions (Gualtieri et al., 2002). In the end, the cyclic AMP/phosphokinase A/CREB pathway represents one of the main target for drug development to treat memory dysfunction (Tully et al., 2003). Dopamine D1/D5 receptors are coupled to activation of the cAMP/PKA/CREB pathway. Thus, D1/D5 receptor agonists may represent an effective pharmacological strategy to activate cAMP signaling to improve synaptic plasticity and memory (Otmakhova and Lisman, 1998). Cyclic nucleotide phosphodiesterases (PDEs) are enzymes, which play an important role in the abovementioned intra-cellular signal transduction pathways. There are 11 families of PDEs (PDE1–PDE11) and most of these families have more than one gene product (e.g., PDE4A, PDE4B, PDE4C, PDE4D). In addition, each gene product may have multiple splice variants (e.g., PDE4D1–PDE4D9). In total, there are more than 100 specific human PDEs. Rolipram, which belongs to the above-mentioned racetams family, is a specific PDE4 inhibitor that has been shown to enhance both hippocampal long-term potentiation, memory transient wakefulness and neuroprotection in mice (Barad et al., 1998 and Block et al., 2001) and long-term potentiation in humans (Rutten et al., 2006 and Rutten et al., 2007).”


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