Schizophrenia The Unwell Brain

Disturbance in the Neurochemistry  The first discovery in the mid 1950s was that chronic usage of large daily doses of Amphetamines could produce a psychosis that was virtually indistinguishable from schizophrenia.  The second discovery was that Chlorpromazine could improve symptoms for schizophrenia.  The effects of Amphetamines and Chlorpromazine on the neurochemistry of the brain were unknown.

Further Discoveries  It was found that Amphetamine could enhance neurotransmission of Dopamine, Norepinephrine and (to a lesser extent) Serotonin Synapses.  It was also discovered that Chlorpromazine could prevent Dopamine from activating it’s D2 receptor subtype.  The knowledge that Chlorpromazine improves symptoms of schizophrenia while blocking D2 receptors for Dopamine has led to the development of drugs that have similar pharmacological properties to chlorpromazine.

Neuroleptics & Atypicals  The Neuroleptics (older generation) are identified in two categories: Phenothiazines & Butyrophenones.  Chlorpromazine (Thorazine) is the original phenothiazine anti-schizophrenic drug.  Haloperidol (Haldol) is the most familiar and widely used butyrophenone.  What do these drugs have in common and what are their effectiveness with treating schizophrenic symptoms?

Positive symptoms  The symptoms that are the most responsive to these types of drugs came to be called the ‘positive symptoms’ because they showed a positive response to neuroleptic drug therapy.  These positive symptoms included: delusions, hallucinations, disorganised speech and bizarre behaviour.  The negative symptoms included: flattened emotional response, impoverished speech, diminished initiative and motivation, social withdrawal, lack of feeling pleasure (anhedonia) and intellectual impairment.

“Problem Schizophrenics”  Newer generation antipsychotics (Atypicals) can be effective in these normally unresponsive schizophrenics. They also lack some of the debilitating side effects of the older neuroleptics.  These newer generation antipsychotics appear to block multiple subtypes of dopamine receptors (including D1 D2 D3 D4 D5); they are also reported to alter serotonin neurotransmission and to effect several other neurotransmitters, including, acetylcholine, norepinephrine, and histamine.

Clozapine (Clozaril)  Clozapine is effective in some schizophrenics whose symptoms do not improve on haloperidol. A patient maintained on clozapine is less likely to show side effects related to involuntary movements (tardive dyskinesia). It tends not to block the receptors for dopamine in the striatum (could explain it’s lack of motor side effects). However it has been observed to have sever negative effects on the immune system  Haloperidol tends to block D2 receptors in the caudate and putamen areas of the brain whereas clozapine blocks D1, D2, D3, D4 and D5 receptors as well as multiple subtypes of serotonin receptors.