Cognitive enhancing agents in schizophrenia and bipolar disorder (2015)

Cognitive enhancing agents in schizophrenia and bipolar disorder

Cognitive dysfunction is a core feature of schizophrenia and is also present in bipolar disorder (BD). Whereas decreased intelligence precedes the onset of psychosis and remains relatively stable thereafter; high intelligence is a risk factor for bipolar illness but cognitive function decreases after onset of symptoms. While in schizophrenia, many studies have been conducted on the development of cognitive enhancing agents, in BD such studies are almost non-existent. This review focuses on the pharmacological agents with putative effects on cognition in both schizophrenia and bipolar illness; specifically agents targeting the dopaminergic, cholinergic and glutamatergic neurotransmitter pathways in schizophrenia and the cognitive effects of lithium, anticonvulsants and antipsychotics in BD. In the final analysis we conclude that cognitive enhancing agents have not yet been produced convincingly for schizophrenia and have hardly been studied in BD. Importantly, studies should focus on other phases of the illness. To be able to treat cognitive deficits effectively in schizophrenia, patients in the very early stages of the illness, or even before – in the ultra-high risk stages – should be targeted. In contrast, cognitive deficits occur later in BD, and therefore drugs should be tested in BD after the onset of illness. Hopefully, we will then find effective drugs for the incapacitating effects of cognitive deficits in these patients.

Substances reviewed include:

Dopamine agonists
D1 agonists (SKF-38939 and dihydrexidine)
D-amphetamine

Glutamatergic drugs
Glycine, D-serine, D-alanine and D-cycloserine
DAAO inhibition (sodium benzoate)
Glycine transporter-1 inhibition (sarcosine and bitopterin)
Ampakines
Lamotrigine
Memantine

Cholinergic drugs
Nicotine
DMXB-A, an alpha 4 and 7 nAChR partial agonist
Alpha 7 nAChR agonists (tropisetron, TC-5619 and RG-3487)
Cholinesterase inhibitors (rivastigmine and donepezil)
Galantamine
M1/M4 muscarinic agonist (xanomelanine)

Other agents (GABA, noradrenergic, serotonergic, histaminergic and cannabinoid receptors)
MK-0777, a GABAA alpha 2 and 3 agonist
5HT1A (partial) agonists (buspirone and tandospirone)
ABT-288, a histaminergic type 3 (H3) antagonist, and MK-0249, a H3 inverse antagonist
Atomoxetine, a selective norepinephrine reuptake inhibitor
Guanfacine, an alpha-2 noradrenergic agonist
Pregnenolone
Modafinil
Rimonabant, a CB1 receptor inverse agonist

Anti-inflammatory drugs
Aspirin
N-acetylcysteine
Davunetide
Minocycline

The authors conclude:

“Despite extensive efforts on the development of cognitive enhancing drugs, to date no putative agents with such properties have been produced for schizophrenia. Antipsychotics appear to mildly improve cognitive function in schizophrenia patients (more in first episode than in chronic patients), but these agents do not improve cognitive function to any meaningful degree. Also, cognitive enhancing effects by dopamine agonists and glutamatergic drugs have been reported. However, results are inconclusive and at best suggest an improvement in cognitive subdomains. Cholinergic agents, in particular galantamine and nicotine, appear to have the most promising cognitive enhancing effects in schizophrenia patients.”


Pharmacological augmentation of cognitive training in schizophrenia (using modafinil) has recently been reported [1]:

“…[the] study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.”

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