Antipsychotic Medications

Author: Paul Merritt

Hello, and welcome to lecture number 11 on our series on drugs and human behavior. Today we are going to be talking about antipsychotic medications. It's obviously a class of drugs that are used entirely for the treatment of mental disorders, in particular schizophrenia. So today we're going to talk about schizophrenia and do a brief introduction to what we think might cause schizophrenia, some of the symptoms associated with schizophrenia, talk about neurotransmitters that might be implicated in schizophrenia, do historical background, and talk about the way we classify antipsychotics-- it's a little strange, truth be told-- talk about the first generation antipsychotics, the second generation antipsychotics, talk about the side effects of those second generation antipsychotics, and then finally finish up with new developments in this area and some other uses for this class of drugs.

So schizophrenia is a particularly debilitating mental disorder. The core features of this particular disease are that for at least six months, the presence of prominent psychotic symptoms, which are presence for at least one week. Their psychosocial functioning is poor. And if they have any present, their mood disturbance is brief versus their psychotic symptoms. So little mood disturbance, with lots of psychotic symptoms. There are three phases associated with schizophrenia, what we call the premorbid phase, where they have subtle motor, cognitive, and social impairments. The prodromal phase is where mood symptoms start to appear. They start to get some cognitive symptoms.

Schizophrenia is associated with a variety of difficulties of frontal lobe functioning. They may also experience social withdrawal or obsessive behaviors. The full syndrome then is substantial functional deterioration in self care, work, and interpersonal relationships. Schizophrenia is considered to be a neural developmental disease. There are significant abnormalities present in both brain structure and function in patients with schizophrenia. It has a high heritability component. There is some current belief that this is an epigenetic disease, that is you have to be born with the propensity for schizophrenia, and then some event triggers the activation of the genes for this particular disease.

And this is a miscommunication syndrome, that is there is a reduction in connections across parts of the brain that result in a variety of symptoms. And finally, quite recently, this has been linked to prenatally nicotine exposure. So there is some evidence that smoking during pregnancy might be that environmental trigger that results in the development of schizophrenia.

Antipsychotic Medications

Again, early to tell, but there is early evidence for that. The symptoms of schizophrenia are classically divided into both positive and negative clusters. Positive symptoms are not good things, but they are the addition of things. Whereas negative things are things that are essentially missing. So the positive symptoms include delusions, hallucinations, thought disorders, the loosening of associations. The hallucinations in this disorder are typically auditory in nature. The hearing voices is sort of the prototypical schizophrenia symptom. Negative symptoms include anhedonia, so an inability to experience joy or pleasure or emotion at all.

They're often withdrawn. They often have limited affect or emotional expression. The treatment focus is primarily in improvement of cognitive functioning and quality of life. So oftentimes limiting hallucinations and trying to improve overall quality of life and cognitive functioning. The classic theory of schizophrenia is primarily one involving dopamine. The disorder seems to have develop from disregulation of dopaminergic brain pathways, resulting in over activity of dopaminergic function. A couple of lines of evidence in this area, the abuse of stimulant drugs increases synaptic dopamine concentrations, such as amphetamine, and can produce a syndrome that's indistinguishable from the paranoid type of schizophrenia.

People hear things, quite paranoid delusions of persecution, et cetera. The antipsychotic drugs we're going to talk about are primarily dopamine receptor antagonists that block dopamine receptors in the brain. And so we know if we reduce dopamine functioning, we treat schizophrenia. If we increase dopamine, we could end up with symptoms similar to schizophrenia. If you look at the treatments used for schizophrenia, you can see that if you look at the-- so haloperidol is the drug that is sort of the reference point in this particular graph.

And what this is just showing you is comparing the percentage for the concentration of the drug that inhibits haloperidol binding by 50%. So you get the same sort of inhibited haloperidol binding. So it's basically showing you that it's taking up the same receptors as haloperidol and what the average clinical dose is. As you can see, that the more receptor sites that the drug is taking up, the lower the dose has to be. So this is a direct relationship between dopamine receptor response and the dose of these particular drugs.

Pretty remarkable. Dopamine, of course, is released by neurons in the basal ganglia of the brain. And it's crucial for maintaining normal coordination of movement. Oftentimes, long-term chronic antipsychotic administration may elicit symptoms of abnormal motor functioning, such as what we call extrapyramidal symptoms or tardive dyskinesia, which is an almost freezing of muscles in sort of grotesque ways. Extrapyramidal symptoms are essentially very similar to what we call pseudo-Parkinson's. Second generation antipsychotics efficacy can be obtained with little or no extrapyramidal symptoms or tardive dyskinesia. So good news, newer antipsychotics can get effective treatment without the side effects of the older generation of drugs.

The clinical evidence for dopamine involvement in schizophrenia, the antipsychotics obviously block dopamine's effect, presumably at the receptor. But, is required for the therapeutic benefit or is that related to the side effects? That's was an open questions there. So the prediction here is if the blockade is required for the therapeutic effect, than drugs that are more potent clinically should also be more potent at blocking dopamine receptors. And we saw that in that graph a minute ago. Serotonin involvement in this disorder, the 5-HT2 receptor and if it's antagonize might be responsible for some of the beneficial actions of antipsychotics.

So antagonism 5-HT2 receptor. Although, it has been concluded that serotonin does not play an important role in the causes schizophrenia, antagonism of 5-HT receptors may be involved in improved neurological side effects profiles of the newer antipsychotic medications. So antagonism of the 5-HT2 receptor may be an important component of this very complicated puzzle. There may be some glutamate involvement in this disorder, as well. Amphetamine, LSD, PCP, and ketamine have provided insight into the neurochemistry of schizophrenia or at least [INAUDIBLE] some of the symptoms associated with schizophrenia, because they can pretty schizophrenia like symptoms. They block the NMDA-type glutamate receptors. NMDA hypofunction results in excessive release of excitatory neurotransmitters glutamate and acetylcholine in the frontal cortex.

Cortical neurons can then be damaged and deterioration triggered. And so we see that in schizophrenia. So this over activation from release of these excitatory neurotransmitters may be involved in this process. So to write a little bit of background, the first category of antipsychotic agents were the phenothiazines. They were initially developed as antihistamines. In fact, the massive sedating effects of these drugs are because of their antihistamine properties. So they have a mildly sedating action or massively sedating action depending on your response. So Promethazine was the first phenothiazine.

Chlorpromzine, which is Thorazine, was really the big first massively used anitpsychotic, and really revolutionized the treatment of this particular disorder. The second generation antipsychotics are the butyrophenones, which came out in the 1960s, like Haloperidol, Droperidol. In the 1980s, Clozapine or Clozaril was used for quite awhile. It has some serious side effects, and let to the development of other atypical antipsychotics, like Risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and et cetera. So there's a pretty significant number of drugs in the arsenal for this. Clozapine is not used anymore, because of its huge side-- or shouldn't be used anymore because of its massive side effect profile. All these second generation antipsychotics differ pharmacologically from the first generation antipsychotics.

They have relatively less affinity for the D2 receptors, and greater affinity for those 5-HT receptors we talked about. This allows the separation between the antipsychotic efficacy and induction of extrapyramidal symptoms for other movement disorders. So if we look at the comparative efficacy, safety, and cost benefit ratio of second generation antipsychotics, while clozapine was superior to first generation antipsychotics, only olanzapine and risperidone appear to be better than those first generation antipsychotics. There are some criticisms of those conclusions, because of differences in dosage and difficulty in patient recruitment. Doing this kind of research is obviously very difficult. This is a relatively rare disorder. Getting access to a population, getting ethically valid studies designed and put together can be very difficult. So I want to take a quick look at a couple of studies to preview some of the issues we're going to be talking about.

The CATIE study, which is the Clinical Antipsychotic Trials of Intervention Effectiveness, with an 18 month study of almost 1,500 patients suffering from schizophrenia at 57 clinical sites comparing perphenzaine with olanzapine, quetiapine, ziprasidone, and risperidone. One of the biggest problems is patients often stop these medications before the end of the study because of side effect profiles. The findings from this study, olanzapine associated with more weight gain or metabolic effects.

It was slightly more effective. Perphenazine was equally effective to all the atypical agents. Risperidone and olanzapine were more effective than the others. Clozapine was more effective than other atypical agents in the treatment of schizophrenia. Unfortunately, its side effect profile makes it almost impossible for so many people to take. The cost utility of the latest antipsychotic drugs in schizophrenia studies are the CUtLASS study, much smaller study.

Primary outcomes for measures of quality of life symptoms, adverse effects, et cetera. Patients with schizophrenia did just as well on antipsychotic drugs from either category. Patients taking first generation antipsychotics showed a trend toward greater improvement on the quality of life scale and symptom scores.

And participants expressed no clear preference. And the costs were similar. So we're really at a loss as what to recommend. It really is a trial and error oftentimes. And so, while drug like Clozaril might not be the best choice because of its side effect profile, it might be something that's worth considering. So there's no clear clinical advantages of the second generation antipsychotics. Over first generations in the treatment of schizophrenia.

There may be advantages in improved relapse prevention, reduced extrapyramidal symptoms, and tardive dyskinesia. And they are possibly useful for treatment of bipolar depression. The problem with the second generations is they tend to be more expensive. They can be associated with weight gain and other metabolic problems. We're going to take a look at some of those side effect issues later on in this discussion. So these are issues to keep in mind as we start looking at these different classes of drugs. So the first generation antipsychotics are the phenothiazines and the butyrophenones.

Oftentimes, these are called major tranquilizers or neuroleptics. They're pretty good at alleviating positive symptomatology. They, however, have no effect on negative symptomologies. They don't approve that flat affect and apathy. They cause parkinsonian type side effects because of their fairly significant dopamine profile. And there are very few non-psychiatric uses for these drugs.

But, there are a few. So, control of nausea and vomiting, for example, is one of those. So one of the drugs we'll talk about here in a moment is used almost entirely for that purpose. These were the drugs of choice up until the mid to late 1990s. In terms of the pharmacokinetics of these drugs, they tend to lipid soluble and highly bound to protein and tissue with large distribution volumes. They have a 20 to 40 hour half life. They're extensively metabolized, and in fact, some of those metabolites can be detected for months after they're discontinued. So a pretty long profile of these drugs.

Let's take a look at this entire list of these drugs. The phenothiazines include Thorazine and compazine, which is almost entirely used for treatment of nausea. Prolixin, Stelazine, Trilafon, Tandol-- all of these are-- Mellaril-- are drugs that are in this early class of drugs. Haldol is the butyrophenone that's primarily prescribed.

And then you get into the newer generations, including Clozaril, Risperdal, Zyprexa, Seroquel, Abilify, all of those. We'll talk a little bit about those. So you could take a look at the autonomic side effects, involuntary movement side effects, and then levels of sedation. So Thorazine has pretty high sedation levels, so does Compazine. The newer antipsychotics. Have low to moderate sedation effects. And the sedating effects tend to have pretty low tolerance.

That is people tolerate them pretty well. So you don't develop tolerance to them pretty quickly. So these first generation antipsychotics drugs block the dopamine 2 receptor, acetylcholine, histamine, and norepinephrine receptors. So by blocking the receptors in the basal ganglia, this is where they produce two kinds of motor disturbances, which includes this acute extrapyramidal reactions and tardive dyskinesia. Side effects include akathisia, which is a restlessness. It seems to be very distressing to most patients. They also can get some dystonia, which is involuntary muscle contractions and substained abnormal, bizarre postures of the limbs, trunk, head, and tongue. And again, this neuroleptic induce parkinsonium.

They get sort of a tremor at rest. It's call it cogwheel type rigidity of the limbs, and slowing of movement with reduction of spontaneous activity. So, pretty difficult to live with side effects.

So tardive dyskinesia is the involuntary hypokinetic movement often of the face and tongue, but also of the trunk and limbs. It can be quite disabling. There's no adequate treatment for tardive dyskinesia. So it's something to keep in mind. [INAUDIBLE] or other second generation antipsychotic can be used instead. Side effects and toxicity.

Sedation, again there's some tolerance to that. Postural or orthostatic hypotension, lower blood pressure, again, some tolerance developed to that. Lowered seizure threshold, which is obviously problematic. Photosensitivity is a massive side effect of Thorazine. And there are, of course, antichoinergic side effects for those that affect the [INAUDIBLE] system, concentration, dry mouth, blurry vision, and some significant memory problems.

So the major adverse effects of the receptor blockade by the neuroleptics, again, D2 receptors, extrapyramidal symptoms, and prolactin release. The norepinepherine is responsible for the postural hypertension. Histamine blockade, sedation, drowsiness, and weight gain.

And the acetylcholine is where we get the memory deficits, some other side effects. And then, finally, the 5-HT, 1B and 2C seem be associated with the weight gain effects for these drugs. So Haloperidol-- when I worked in mental health long, long ago, this was the drug that was most often given. It was introduced in 1967 as the first alternative to phenothiazine. It blocks the D2 receptors.

Again, this also causes Parkinsonism and other motor disorders, comparable to those induced by high potency phenothiazine. Moban and Loxitane were introduced in the '70s. Loxapine binds strongly to both dopaminergic and serotenergic receptors.

Orap is used for treatment of motor and phonic ticks in patients with Tourette's disorder. But really, Thorazine and Thioridazine and Haloperidol are the primary drugs used for treating schizophrenia from this class. In the second generation antipsychotics, we start with a Clozapine. This reduces symptoms in about 30% of those who do not improve with standard drugs. So it's a good drug of sort of last resort.

It practically produces no Parkinsonian side effects or tardive dyskinesia, meaning patients who also could not tolerate other drugs because of these side effects can be helped by Clozapine. It also may reduce negative symptoms. It's action is that non-dopamine receptors produces non-therapeutic effects, so that histamine antagonism produces drowsiness and weight gain. The alpha-adrenergic 1 antagonism causes dizziness and decreased blood pressure. It's anticholinergic blockades causes drowsiness, hypersalvation, blurred vision, constipation, and significant cognitive impairment. The greatest concern with Clozapine is the risk of developing severe life threatening agranulocytosis, which is a loss of white blood cells, which can be obviously very problematic. About 40% of patients report significant sedation, which results in very little compliance for this drug.

The other major problem is 80% of patients gain 20 pounds or more. It's not unusual for this particular drug. It's the least prescribed, and really has some of the worst side effects of the antipsychotics.

Risperidone or Risperdol is a 5-HT2 and D2 blocker. And the latter, D2 blocker improves antipsychotic and reduces extra pyramidal effects. It has an active intermediate, which is 9-hydroxy risperidone, which has a half life of 23 hours.

Side effects of this drug include agitation, anxiety, insomnia, headache, nausea, extra pyramidal symptoms at higher doses. It's uses include, as a first line drugs, especially when negative symptoms predominate in the first episode. It's indicated for the treatment of schizophrenia, bipolar disorder, and irritability in individuals with autism. It's pharmacodynamic. It results in reduced aggressive, depressive symptomology, and increased energy, and global functioning in patients with borderline personality disorder. It has a long acting injectable form, which is now available. It's encapsulated in biodegradable polymer microspheres in a water-based solution.

So when you inject it, these dissolve over time. A single intramuscular dose can last for up to two weeks. Zyprexa is like Clozapine, but devoid of the white blood cell metabolism from a toxic intermediate. And has a D2 and 5-HT2 blockade, the latter is much greater. Improves both positive and negative symptomology. Side effects include weight gain, almost as much as Clozapine, sedation, dizziness, orthostatic hypertension. Intramuscular version is shown to be superior for severe agitation and bipolar mania and schizophrenia. Seroquel is the fifth atypical 5-HT2 D2 antipsychotic that became available.

It's comparable to haloperidol on producing positive symptoms with few extra pyramidal symptoms. There are long acting versions. It's approved for use in acute and maintenance treatment of schizophrenia, bipolar disorder, and as an adjunctive treatment for major depressive disorder, and bipolar disorder maintenance, and adolescent mania. It's shown to be superior to valproate in treating mania. So we'll talk about valproate, when we get to talking about bipolar disorder. The second generation antipsychotics have pretty terrible side effects or potential. One of the most significant of those is weight gain.

Animal studies examining drug actions on the lateral hypothalemic neurons that express directions orexins, which are proteins involved in feeding stimulation and weight regulation, Clozapine, risperidone, and olanzapine increase orexin activity. Whereas, Haldol, ziprazidone, and amphetamine do not. This suggests increased orexin secretion may underlie weight and appetite gains of certain atypical antipsychotic drugs. And so it's through this other protein that you get the side effects of weight gain.

If you look at the percentage of participants showing weight gain, you can see aripiprazole, which is Abilify, is at about 20% percent, versus Clozapine, which is about 54%. In 2003, use of atypical antipsychotics was associated with the development of diabetes. At the time, it's not known if these drugs affect glucose metabolism or increased risk factors. It's been shown that Zyprexa impacts glucose metabolism independent of weight gain.

There are increases in plasma glucose levels of fasting and after the glucose challenge, even in non-obese patients. So it's very clear that this drug is causing some risk of diabetes. Risperidone is much less riskier for this particular side effects than olanzapine. One of the biggest problems with the second generation drugs, and even some first generation drugs, are sudden cardiac death. It's caused by a drug induced QT interval prolongation. Without getting too far down the rabbit hole on reading the electrocardiograms of patients on antipsychotics, suffice to say that it is associated with the beats of the heart.

You get this what's called twisted points arrhythmia, torsades de pointes. And the antipsychotic most associated with this is Thioridazine. So it can be potentially dangerous. So new developments in this area there are two drugs here in clinical testing with D3 and D2 partial agonists that show little weight gain or metabolic problems, and another of high D2 receptor occupancy and low 5-HT receptor blocking. Other potential uses for antipsychotic medications include bipolar disorder, unipolar depression, delusions and aggression in dementia, autism spectrum disorders, PTSD, obsessive compulsive disorder, borderline personality disorder, and Parkinson's disease. In terms of the applications that these are approved for, Abilify is approved for acute mania or mixed episodes of bipolar disorder, good for maintenance therapy, and possibly resistant depression, irritability, and autism.

So you can see some of these drugs are associated with treatment for bipolar and other resistant depression. So sometimes olanzapine team can be combined with fluoxetine as a way to treat resistant depression. So most of these drugs are useful in treating bipolar disorder.

Only a few of these drugs are as additions to current treatment are thought to be useful in a unipolar depression. We'll talk about depression next. Delusions and aggression in dementia, unfortunately, these drugs will worsen the cognitive symptoms associated with dementia. For patients who are autism spectrum disorder patients, these are only useful in treating aggression in stereotypic behaviors. For PTSD, only treatment of psychotic symptoms.

For obsessive compulsive disorder, the second generation antipsychotics have been shown to be effective in treatment OCD, generalized anxiety disorders, and panic disorders. There seems be no effect for most of these on borderline personality disorder. Mood stabilizers have been shown to have some benefit. And then, finally, Parkinson's, quetiapine is the preferred treatment there. So these drugs have a lot of other uses, some of them are better than others.

And so certainly look into these if there are things you are interested in. Well, thank you. That is our discussion of antipsychotics. We will be talking about antidepressants next.

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