In the 1950’s, a molecule named chlorpromazine was
discovered and was intended to be used as a pre-anaesthetic
drug. It came into observation by psychiatrists that it reduced
positive symptoms in schizophrenic patients. It later led to the
discovery of the molecular explanation of schizophrenia by
understanding the pharmacology of the medication: this
molecule causes a reduction in the dopamine activity in the
brain! Therefore leading to the logical conclusion that
schizophrenia is mainly due to an excess in the activation of this
system. This theory has won Carlson a well-deserved Nobel
Prize in the early 1960’s.
This inconvenience is explained by the following fact: their
antagonizing activity is not directed to the mesolimbic
receptors speci�ically, and ends up acting on all D2 receptors in
the brain causing side effects. When they block D2R in the
striatal pathway, we have extrapyramidal symptoms
resembling those of Parkinson’s disease, and when they block
D2R in the tubero-infundibular pathway, they lift all inhibition
on prolactin’s release by the pituitary gland, thus causing
hyperprolactinemia.
Later came Clozapine and its comrades, known as atypical
neuroleptics, which won themselves the “atypical” adjective
because they reduce positive symptoms without causing EPS,
contradicting thus the same theory that explains their
mechanism of action. However, that could be explained by the
following notion: These drugs not only block D2R in a more
speci�ic way than the previous family, they also have a
muscarinic and serotonin-like activity that reduces the side
effects caused by D2R general blockade. This effect is due to the
fact that the serotoninergic and muscarinic systems cause a
release of dopamine, which lessens the side effects by
counteracting the excessive blocking of the other pathways.
Nevertheless, they do not come without cost. Their most
undesired effect is weight gain, metabolic syndrome, diabetes
mellitus and cardiovascular disease, which is the �irst mortality
cause among this group of patients.
Let us talk about dopamine. There are two kinds of dopamine
receptors in the central nervous system: D1 receptors and D2
receptors. The latter type can be found in various regions and
pathways of the brain: in the mesolimbic pathway, in the
striatal pathway and in the tubero-infundibular pathway. The
former type are mostly found in the mesocortical pathway. Each
pathway has a certain function: the nigrostriatal pathway is
important in motor control; the mesolimbic pathway, running
from groups of cells in the midbrain (or mesencephalon) to
Hopes for the future
parts of the limbic system is involved in emotion and reward ;
the mesocortical pathway, that runs from the midbrain to the
cortex, involved in emotion and decision-making and the
tuberoinfundibular neurons, running from the hypothalamus
to the pituitary gland, whose secretions they regulate.
It is treatable, isn’t it?
The many molecules that came after were very similar to
Chlorpromazine in their pharmacological activity, and
constituted a family known as typical antipsychotics. They have
more important antagonizing activity on the D2R than that on
the D1R, but they have all the side effects that come with
blocking the majority of these receptors, especially the
extrapyramidal syndrome (EPS) which is most bothersome to
both patients and doctors putting often an end to treatment.
Chlorpromazine was the �irst in a long line of antipsychotics to
be discovered, as we have said before. Because schizophrenia’s
positive symptoms are due to an excessive dopamine activity in
the D2 receptors, present in the mesolimbic pathway,
antagonizing dopamine’s activity in this region would be the
logical way with which the medicine must proceed in order to
reduce those symptoms. Their activity however does not
extend to the mesocortical pathway, because the predominant
receptors there are the D1 receptors, which explains their little
effect on negative symptoms.
20
Having talked about the leap made by neuroleptics’s use in the
treatment of schizophrenia and their effectiveness on positive
symptoms, the problem of negative symptoms remains the
same, as both typical and atypical antipsychotics do little in this
regard. It is in fact one of the major �laws in the dopamine
theory, that seems to explain only a part of schizophrenia’s
symptomatology. It is not a surprise that another theory is
being considered. A theory known as the glutamate theory: It
has been observed, 20 years ago, that substances such as
ketamine and phencyclidine that act by antagonizing certain
NMDA receptors (N-Methyl D-aspartate), belonging to the
glutamate system, produce positive and negative symptoms
similar to those found in schizophrenia. It is very suggestive
that the illness is due to a defect in these NMDA receptors.
Glutamatergic neurons and GABAergic neurons play complex
roles in controlling the level of neuronal activity, in b oth the
mesocortical and the mesolimbic dopaminergic pathways.
NMDA receptor hypofunction is thought to reduce the activity
in mesocortical dopaminergic neurons. This would result in a
decrease in dopamine release in the prefrontal cortex, and
causes negative symptoms of schizophrenia. On the other hand,
NMDA receptor hypofunction is thought to elevate the level of
activity in the mesolimbic dopaminergic pathway, perhaps
because NMDA receptors are located on GABAergic
interneurons, which have an inhibitory activity. Thus NMDA
receptor hypofunction would result in reducing the GABAergic
inhibition of mesolimbic dopaminergic neurons and therefore
give rise to elevated dopamine release in limbic areas, resulting
in the production of positive symptoms .That is why, it has been
suggested that the possible solution lies in creating a drug that
can induce a glutamate-like effect in this dysfunctional system.