Antipsychotics and Schizophrenia

I'm not sure how easy (or not) it will be to write this post, given that this lecture went seriously overtime and the lecturer had to skip a good chunk of the slides. This guy has been seriously optimistic about how much he can cover in 45 minutes, but oh well.

Understand what Schizophrenia is

Schizophrenia is a mental illness with a range of symptoms. Here are the symptoms that are listed in the ICD-10 classification:

1. Thought echo (repetitive thoughts), thought insertion (belief that others can insert thoughts into your mind), thought withdrawal (belief that others can remove thoughts from your mind) and/or thought broadcasting (belief that your thoughts may be transmitted to others)
2. Delusions of control, influence or passivity, delusional perception
3. Hallucinatory voices
4. Culturally inappropriate delusions. These include persecutory delusions (belief that you are being persecuted), grandiose delusions (belief that you are super important in some way) and delusions of reference (belief that mundane things are very significant- for example, believing that a television commentator is talking directly to you). These do not include particular religious or political beliefs.
5. I don't really know what this one means so I'm going to copy it word for word. "Persistent hallucinations in any modality, when accompanied either by fleeting or half-formed delusions without clear affective content, or by persistent over-valued ideas, or when occurring every day for weeks or months on end."
6. Incoherent or irrelevant speech, neologisms (either making up words or using real words in a completely wrong way)
7. Catatonic behaviour. I'm also not really sure how this is defined because it seems to encompass a wide range of things: excitement, posturing (a.k.a. "wavy flexibility," where you can move the person around in a random pose and they'll just hold it), negativism, mutism and stupor
   EDIT: I found a good clip that explains catatonia





"Negative symptoms," i.e. things that a normal, healthy person would exhibit but a person with schizophrenia would not. These include apathy, paucity of speech, blunting or incongruity of emotional responses and social withdrawal
Significant and consistent change in personal behaviour

Additionally, you need to rule out other things that could cause these symptoms, like brain disease, drugs and so on.

Schizophrenia can progress in many different ways. It can be continuous or episodic, progressive or stable. There may be incomplete or maybe even complete remission between episodes.

Be familiar with what is known (or perhaps unknown) about the pathology of schizophrenia

A long time ago, people thought that demonic possession or even masturbation were the causes of schizophrenia. Thankfully, we've moved past that, but we still don't really know what the true causes are. Between 1925-1967, scientists thought that they found some brain changes, but they soon changed their minds and decided that there were no changes that they could see. In the 90s, schizophrenia came to be associated with ventricular enlargement and decreased cortical volume, but later these changes were found to be associated more with antipsychotic use rather than the illness itself.

Be familiar with the Dopamine Theory of Psychosis

Since all effective treatments for psychosis block dopamine D2 receptors, and drugs that increase dopamine transmission (like amphetamine) can induce psychosis, it makes sense that too much dopamine can cause psychosis, right? Furthermore, patients with schizophrenia, as well as patients deemed to be at ultra-high risk of developing schizophrenia ("ultra-high risk" in this case means that they have already developed some psychotic symptoms, but not full-blown schizophrenia), have increased synthesis and release of dopamine compared to healthy controls.

There are multiple pathways involved in the release of dopamine, including the mesolimbic and mesocortical pathways. Some scientists believe that an increase in dopamine transmission in the mesolimbic pathway is responsible for psychosis, whereas a decrease in dopamine transmission in the mesocortical pathway is responsible for the "negative" symptoms (such as apathy and social withdrawal).

Know the differences and similarities between Typical and Atypical Neuroleptics

This part is going to be watered down, given that the lecturer didn't have time to cover it in detail.

First things first: neuroleptics, antipsychotics and major tranquillisers all refer to the same drugs.

The first neuroleptics developed are known as the "typical neuroleptics." They are all very effective D2 antagonists. The therapeutic effects are due to antagonising D2 in the mesolimbic system, whereas side effects are thought to be from D2 antagonism in the nigrostriatal system (part of the extrapyramidal motor system, so these side effects are also known as "extrapyramidal side effects"). And oh boy, the side effects do not sound pleasant:

• Parkinsonism (muscular rigidity, slow movement, tremor)
• Acute dystonic reactions (abnormal movements)
• Akathisia (restlessness)
• Neuroleptic malignant syndrome (high fever that may lead to death- pretty rare but obviously pretty nasty)
• Cardiovascular effects such as long QT, which may lead to heart failure
• Tardive dyskinesia (writhing movements, particularly of the feet, hands and/or tongue)

The next lot of neuroleptics are known as the "atypical neuroleptics." They generally have fewer extrapyramidal side effects as compared to the typical neuroleptics. The first atypical neuroleptic was clozapine, which was found to have greater therapeutic effects, even in treatment-resistant patients. Unfortunately, it also has really bad side effects, like agranulocytosis (which is potentially fatal), so now it is mainly used for treatment-resistant patients under close monitoring.

Clozapine, like the typical neuroleptics, acts mainly by D2 antagonism, though it has a lower affinity for these receptors. It can also antagonise other receptors, such as D1, D4, 5-HT2A, muscarinic, histamine and alpha-adrenergic receptors. Other atypical neuroleptics, such as olanzapine, respiridone and quetiapine, also have a decreased affinity for D2 receptors and can bind to other receptors, such as 5-HT2A. It is thought that 5-HT2A antagonism may help to reduce the risk of extrapyramidal side effects. One exception to the "D2 antagonism rule" is aripiprazole, which actually works by acting as a partial agonist of D2 receptors, which is weird but okay. I think the lecturer said something about why this works, but he was in a real hurry to move along to the next slide because we were already overtime by this point.

Atypical neuroleptics also have a lot of side effects. While neuroleptics other than clozapine don't have issues with agranulocytosis, obesity, type II diabetes and cardiovascular problems may all be problematic.

Comprehend Seeman’s Occupation of dopamine D2 receptor hypothesis

Seeman developed a hypothesis that states that the best antipsychotic action occurs when D2 receptors are 65-80% occupied. When more than 80% of D2 receptors are occupied, extrapyramidal side effects may occur. The possible implication of this is that, if you reduced the dose of a typical neuroleptic so that less than 80% of D2 receptors are occupied, perhaps they would become equivalent to atypical neuroleptics.