Module 40

Question 1

Try to relate the effects of hallucinogens and related agents to possible mechanisms of schizophrenia and also to mechanisms of the antipsychotic drugs.

Answer 1

• The classic hallucinogens such as LSD, phencyclidine, psilocybin, and mescaline bind to serotonin and dopamine receptors. Most are quite “dirty” and bind to many receptors, so it is hard to draw clear conclusions, but this observation led to hypotheses of the mechanism of schizophrenia and possible treatments. Clinical studies, which would not be approved today, were done with agents such as LSD to study its effects

Question 2

Do you believe the structure below, which has been reproduced from Figure 28-8 in the previous edition of the UofT textbook, in terms of where the proton and + charge are on this molecule? It is also stated that it cannot enter the brain because of the + charge. Does that seem likely from its structure? What limits the CNS effects of domperidone?

Answer 2

• Obviously the protonated nitrogen in this figure is both an amide nitrogen and attached to an aromatic ring; therefore, it would not be basic. The structure should be the one shown below.
  The reason that domperidone has limited CNS effects is that it is a good substrate for the transporter P-glycoprotein and is efficiently pumped out of the brain.

Question 3

Why are older antipsychotic agents associated with extrapyramidal side-effects, but clozapine is not? How does the therapeutic efficacy of clozapine compare with other antipsychotic agents? What is the most common serious adverse reaction associated with clozapine?

Answer 3

• The first major antipsychotic agents were phenothiazines. They were being developed as antihistamines, but they were found to have calming effects.
  ○ Phenothiazines are dopamine D2 antagonists, and subsequent drugs were developed based on binding to D2.
  
  • Then clozapine was developed and found to have little affinity for D2, but rather bound to the dopamine D4 receptor, and it was not associated with significant extrapyramidal side-effects.
    ○ Clozapine also binds to several serotonin receptors.
    ○ Clozapine is the most efficacious antipsychotic known, and some schizophrenic patients become almost normal when treated with clozapine. However, it is not understood why it is more effective, i.e. what combination of receptor affinities are important.
  • Newer analogs such as olanzapine are just not as effective, although each patient is different. However, clozapine is a 3rd line drug, i.e. patients have to fail on two other agents first.
    ○ That is because it can cause agranulocytosis (incidence about 0.2%) and patients who take the drug have to have their neutrophil counts determined every week for the first several months on the drug (policy of no blood no drug). This can be quite a challenge in the patient population involved. I think clozapine is underutilized because, despite the risk of agranulocytosis and it being used in the most severely affected patients, the overall mortality of patients on clozapine is actually less than that of patients on other agents. The reason: the major cause of death in these patients is suicide, and because of the effectiveness of clozapine, the risk of suicide is lower.

Question 4

A patient was treated with clozapine with a good response for more than a year. Then suddenly the patient developed symptoms of clozapine overdose with somnolence, hypersalivation, and extreme fatigue. What habit would you enquire about to try to determine the cause for the change in response?

Answer 4

• You should find out if the patient smokes and whether they had recently stopped. The incidence of smoking is higher among patients with schizophrenia.
  
  • Smoking induces the metabolism of clozapine and olanzapine, and if a patient stops smoking it will lead to a significant increase in their blood levels. On average, doses of clozapine should be reduced by 30-40% in patients on the drug if they stop smoking

Question 5

What is the serotonin syndrome, and what are risk factors for its induction?

Answer 5

• The serotonin syndrome is characterized by an increase in body temperature, agitation, tremor, increased reflexes, sweating, dilated pupils, and diarrhea. As the name implies, it is caused by agents that increase serotonin levels in the brain.
  ○ This includes selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, tricyclic antidepressants, amphetamines, demerol, tramadol, St. John’s wort, triptans, etc.
  ○ The serotonin syndrome can lead to seizures and is potentially fatal. It usually occurs in the context of an overdose or the combination of two agents that increase serotonin.
  
  • Therefore, in filling prescriptions you should note if two or more agents are being prescribed in combination that increase serotonin levels. In some cases such combinations are rational, but caution is warranted. Serotonin syndrome can be hard to differentiate from neuroleptic malignant syndrome.

Question 6

What is one of the most significant chronic metabolic side effects of most of the newer antipsychotic agents?

Answer 6

• The newer antipsychotic agents such as olanzapine and clozapine generally cause significant weight gain (10-20 lbs or even more), and they increase the risk of diabetes and metabolic syndrome.