In my research concerning schizophrenia, I have long been confused as to how antipsychotic mediations work.  To the pharmaceutical layman, words like “first generation” and “second generation antipsychotics” might ring with some kind of familiarity.  Many individuals know that antipsychotics have come a long way, but what exactly is it about these newer antipsychotics that make them more desirable, and how exactly do they work?  To answer this question, I found a perfectly suited article titled [the] differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus, and yes the grammar in the title is really that bad, but please don’t let that turn you away from the validity of the study.

In this experiment, the researchers utilized two drugs and studied their contrasting effects on endogenous growth factors (VEGF).  Haloperidol (HAL] was chosen with the intention of illustrating a typical “first generation antipsychotic,” while Olanzapine (OLZ) served as a second generation representative.  Because of the known effect that these drugs both seem to have on hippocampal levels of VEGF, the researchers chose to measure levels of these neuropeptides as well as concentrations of its receptor, FLK-1.  Both of these factors serve as measures of angiogenesis, or growth of the blood vessels; so this factor was measured as well.

To test possible effective discrepancies, the researchers assembled two cohorts of lab rats; each administered either HAL or OLZ.  In each group, the rats were either sacrificed after 14 days or 45 days to study the long and short-term effects of the drugs.  With regard to the aforementioned dependent measures, the results were quite interesting.

The researchers found that, after 14 days, the HAL treatments significantly increased VEGF and FLK-1 quantities in the hippocampal tissue.  Furthermore, the HAL had an even more pronounced effect than OLZ in increasing VEGF levels.  This is interesting because it might alone suggest that first gen antipsychotics work better than their second-generation counterparts; however, the rest of the findings paint a different picture.  After 45 days, the HAL treated rats returned to completely baseline levels of VEFG and FIK-1 receptors.  Moreover, the OLZ treated rats expressed even more VEGF than before.  The findings with regards to levels of angiogenesis were similar.

Ultimately, these findings suggest that, while first generation antipsychotics seem to have a stronger initial effect, the more subtle and long-lasting effects of the second generation ones might yield more desirable behavioral results.  Furthermore, the initial spike seen in the HAL treated groups might be representative of the human self-reports of the more intense negative side effects that occur when using Haloperidol.  Both generation drugs ultimately increase angiogenesis in the hippocampus, the center for learning and memory.  Because this structure is known to deteriorate in correlation with the onset of schizophrenia (we don’t know if the deterioration causes the disorder or vice versa), antipsychotics largely work by increasing blood flow, effectively stalling this decay.  These findings seem clean enough, however, it certainly does not completely answer the initial question because it does not address every system that influences or is influenced by antipsychotics.  For example, dopamine 2 receptors, important in the reward pathway of the brain, are also affected.