11 de noviembre de 2011

Treatment-resistant schizophrenia: Memantine

An alternative to the dopamine model was first proposed
in the early 1990s, based upon the observation
that phencyclidine (PCP), ketamine and other similarly
acting psychotomimetic compounds induced their
unique behavioral effects by blocking neurotransmission
at N-methyl-D-aspartate (NMDA)-type glutamate
receptors. The ability of these
compounds to transiently reproduce key symptoms of
schizophrenia by blocking NMDA receptors led to the
concept that symptoms in schizophrenia may reflect
underlying dysfunction or dysregulation of NMDA
receptor-mediated neurotransmission. This model has
been increasingly adopted and is now considered to be
one of the useful models for both etiological conceptualization
of schizophrenia and new treatment development.
NMDA receptors are composed of a combination of
distinct subunits termed NR1, NR2 and NR3. Multiple
splice variants of the NR1 subunit have been described,
along with multiple subforms of the NR2 subunit
termed NR2A-D. All functional NMDA receptors possess
one or more NR1 subunits. In addition, most receptors
contain a combination of NR2 subunits, with NR2A
and NR2B subunits dominating in adult brain. Different
combinations of subunits confer different properties to
the receptors. It has been suggested that NR2A and
NR2B subunit-containing receptors may have differential
roles in psychogenesis, although others
have suggested that combined blockade is needed.
Because of the lack of subunit specific drugs, it is difficult
to determine the involvement of the different subunits
types in the pathophysiology of schizophrenia and
it remains possible that subtype-selective intervention
will prove preferable to generalized modulation across
NMDA receptor subtypes.

Glutamate-dopa mine Glutamate-GABA Interactions

Finally, NMDA dysfunction may also account for both
the impaired dopaminergic regulation and the impaired
GABAergic neurotransmission that has been documented
in schizophrenia. Dopaminergic dysfunction
has been studied most extensively using positron emission
(PET) or single photon emission (SPECT) markers
of response to amphetamine. In such studies, D2
agonists are tagged with appropriate radionuclides and pattern of displacement is evaluated
following amphetamine administration. Across cohorts,
patients with acute schizophrenia show enhanced
striatal dopamine release to amphetamine challenge,
consistent with presumed dysregulation of subcortical
dopamine circuits.
Deficits similar to those observed in schizophrenia
are observed in normal volunteers undergoing ketamine
infusion, and in rodents treated subchronically  with NMDA receptor antagonists, suggesting that
dopaminergic dysregulation in schizophrenia may be
“downstream” of a primary deficit in NMDA function.
Similarly, NMDA antagonists alter the random firing
rate of rodent prefrontal neurons while decreasing burst
firing, also supporting the concept that deficits in
NMDA transmission may lead to the widely cited disturbances
in prefrontal function in schizophrenia.
Changes in GABAergic neurotransmission have also
been increasingly well documented over recent years,
with studies showing reduced parvalbumin and GAD67
expression, particularly in prefrontal cortex  and
hippocampus. Similar effects are seen in both
rodents  and monkeys  treated with NMDA
antagonists such as PCP, as well as in cell culture.
GABAergic dysfunction in PFC may be directly linked
to well-documented deficits in working memory function,
and may therefore represent an appropriate target
of pharmacological intervention. Nevertheless, etiologically
such abnormalities may reflect downstream
effects of primary deficits in NMDA receptor-mediated

Augmentation with NMDA agonists

Like anticonvulsants, the use of N-methyl-D-aspartate (NMDA) -enhancing agents is predicated on the glutamate hypothesis of schizophrenia, specifically NMDA receptor hypofunction. Antagonists of NMDA receptors such as phencyclidine and ketamine produce psychotic symptoms and neurocognitive deficits in human subjects and exacerbate psychotic symptoms in people with schizophrenia. Agonists at the obligatory NMDA-glycine binding site are glycine, D-serine, and D-alanine and the partial agonist D-cycloserine, as opposed to agonists at the NMDA recognition site, which are excitotoxic. These agents, in addition to sarcosine which increases the availability of glycine in the synapse by inhibiting the glycine transporter-1 (GlyT-1), have been investigated as potential therapeutic agents for schizophrenia. Tsai and Lin performed a meta-analysis of 26 double-blind, placebo-controlled trials in approximately 800 people taking an NMDA agonist in addition to stable doses of antipsychotic medication for at least 4 weeks Almost all studies used the PANSS to assess symptom severity. The pooled effect size of clinical efficacy of NMDA agonist augmentation compared with placebo for total psychopathology was 0.40 (95% CI 0.22–0.58) and significant improvement was noted for depressive, negative, cognitive, positive, and general symptoms. Treatment with glycine, D-serine, and sarcosine was associated with improvement in multiple symptom domains while D-cycloserine was not. The concomitant antipsychotic used appeared to affect the efficacy of the NMDA-enhancing agent; those treated with risperidone or olanzapine improved, but those treated with clozapine did not. Gastrointestinal (GI) upset and nausea were noted more often in some glycine trials while other side effects were equivalent for NMDA-enhancing agents and placebo. Despite a moderate effect size, the efficacy of these agents may have been overstated due to limitations within the study. For instance, studies were included only if they provided “enough data to calculate the effect size” and a test for homogeneity revealed that there may have been systematic differences among the included studies. Another important caveat is that D-cycloserine, D-serine, D-alanine, and sarcosine are protected by US patents for which the study author is a patent holder.

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