Antischizophrenic activity independent of dopamine D2 blockade.
Currently, the drug therapy of schizophrenia consists of blockade of central dopamine D2 receptors. There is, however, an urgent medical need for alternative, more effective treatments. Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). Similarly, several pharmacological principles are conceivable to enhance neurotransmission at NMDA receptors (catechol-o-methyl transferase inhibition, glycine uptake blockade, glutathione suppletion and others). In this review, the possible pharmacological approaches and their respective advantages and disadvantages are discussed.
Kalkman
Hans O
HO
Novartis Pharma AG, Research Nervous System, Building WSJ-360-405, CH-4002 Basel, Switzerland. hans.kalkman@pharma.novartis.com
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors; D000818:Animals; D014150:Antipsychotic Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D001923:Brain Chemistry / Q000187:drug effects*; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000134:cerebrospinal fluid / Q000502:physiology; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000009:adverse effects / Q000494:pharmacology; D000077213:Lamotrigine; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D027981:Symporters / Q000037:antagonists & inhibitors; D014227:Triazines / Q000494:pharmacology
D027322:Amino Acid Transport System X-AG; D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D050491:Glutamate Plasma Membrane Transport Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D027981:Symporters; D014227:Triazines; D018698:Glutamic Acid; D007649:Ketamine; D000077213:Lamotrigine