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Essential features of schizophrenia include psychotic features which are present for at least one month. Secondly, a person has to be functioning below their highest level, or if it’s early onset, below a level of what we would expect them to achieve in adulthood. Finally, to make a diagnosis, we wait until it has been present for six months. What’s important is that the six month duration does not mean psychotic symptoms for six months. It’s the presence of this illness which can include prodrome and psychotic symptoms, and also once psychotic symptoms are in remission, the continued downhill course. So the deterioration of functioning usually starts in the prodrome, which may last one, two or three years, and then continues with psychosis.
Now the definition of the active phase - this is a slightly simplified version - the simplified version is any two or more of this list of psychotic symptoms, plus negative symptoms, which again are recent additions to the list. So psychotic symptoms, delusions, hallucinations, disorganized speech, disorganized behavior or negative symptoms. The reason I’ve simplified it is actually if a person has the cardinal features, which are bizarre delusions, delusions which are totally implausible, or have the classic hallucinations which are two voices carrying on a running commentary. Or two voices which are talking back and forth. Then it’s enough to have just one of those two, the bizarre delusions or classic hallucinations.
I mentioned the prodrome. The prodrome is crucial. It’s very important for a number of reasons. This list is actually not contained in the DSM-4. I had to go back to the DSM-3-R for a list of symptoms of prodrome. One reason that it is no longer listed is that it’s so non-specific. The classic prodrome is a student in college, first semester, that just begins to do poorly. That begins to fail in school. Develops some of the negative symptoms of apathy, social withdrawal. Often you see sort of quasi-psychotic symptoms. They are not fully psychotic, but they may become just somewhat bizarre. Start showing interest in sort of strange fringe beliefs. In most cases the family assumes that their child has gotten into drugs. And the prodrome, because it’s non- specific, it’s not frankly psychotic, it often takes a year or two before we understand why this young adult.
The reason why the prodrome is so important, number one, is it is such a frustrating, difficult syndrome for families and clinicians to try to sort out, but there is growing evidence that if we can catch this illness in the prodrome, particularly with the newer antipsychotic agents.
Disorganized type, in the past was known as hebephrenic schizophrenia, characterized by disorganized speech and behavior. These are the patients who may become sexually inappropriate in disrobing and masturbating in public. Sometimes dangerous or violent just because of their disorganization. Along with disorganization we see inappropriate affects as those two symptoms seem to run together. In a few minutes I’ll be talking about the prognosis, which differs with these different subtypes. The subtype of which Kraepelin emphasizes as probably being a distinct, separate subtype - and in my clinical experience I am very impressed that this group really stands apart - is the paranoid subtype. And paranoid schizophrenia is characterized usually by systematized delusional systems which don’t have to be paranoid, but a single delusional system.
Finally, delusional disorders, or paranoid disorders, are psychotic disorders which are non-bizarre. Usually without auditory hallucinations. Usually without the global deterioration in functioning. The delusional disorders seem not to group with schizophrenia, in terms of family studies or even in terms of responsive treatment. It seems to be a separate group of disorders.
The evaluation of someone with a major psychotic disorder, exactly as you would expect. First we want to rule out organic etiologies. It’s very important to take a complete history, both psychiatric and medical, physical exam and neurological exam, mental status exam, and any sign of localizing cognitive deficits. It’s a good idea to get neuropsychiatric testing. But as I’ll talk about, we do see certain general cognitive deficits in schizophrenia. Full laboratory screening. I’ve listed the tests that we do. Obviously, don’t forget about HIV testing when appropriate. You can see occasionally psychotic symptoms as the first presentation of HIV. Toxic screening, very important.
Now I’d like to shift and sort of just describe the prevalence and course of the illness, and some of the characteristics. Now if you were to take an exam, the answer is 1%. That’s the simple answer to prevalence of this illness. It may be a little more complicated, or at least it’s a little more interesting. I’ll show you a slide in a second by the regional variation, which has been studied pretty extensively in the U.S. The highest incidence is among the urban poor. You’ve probably all heard of "schizophrenia drift". And schizophrenia drift just refers to the fact that as people develop the illness they tend to sort of migrate to cities and then sort of drift down the food chain and become the urban poor. So that evidence does not suggest that being poor and urban is a cause of the illness, rather that’s where patients end up.
Then finally, there have been several studies of which you should be aware. Some fairly compelling suggesting that the incidence of schizophrenia has been steadily dropping over the last 20 or 30 years. This has now been repeated in several countries. Again, no one is sure why. Some people think it may be from increased immunization for viral illnesses. This is a typical plot of the incidence or the prevalence of psychosis in the United States. For many years, starting around the early 1800’s, the U.S. conducted the census for the insane every ten years.
The form that is getting a lot of attention is in so-called gating or filtering of auditory input, and I’ll talk a bit about the P-50 test in the next slide. Also the P-300 potentials show abnormalities and the P-300’s have also been correlated with symptoms in patients with the illness. This is the P-50. I just found this particular study, which has not been fully replicated, sort of a fascinating example. Basically the P-50 paradigm is studying filtering by … a person is given a series of paired clicks or sensory stimuli. The first click, which is followed on the P-50 wave form. You can see the wave form reflecting brain processing of this first click, and then after a set pause there is a second click and you can see the second wave, which would be right there, is attenuated. And this is basically because after hearing several hundred paired clicks the brain learns to accommodate. It learns not to process the second click in the same way as the first, because the brain anticipates it and it is filtered out. Essentially a non-novel stimulus. The closest you can describe it is, say if you walk into your bedroom.
That’s kind of a long-winded explanation but there is a ratio of the magnitude of the second wave form over the first wave form, with zero being normal - meaning no response to the second - and numbers up around 100 or greater being associated with schizophrenia. In this pedigree a normal woman with zero, which is a normal ratio, marries a man with schizophrenia with an abnormal ratio and inability to filter. They have four children. You can see the son, only one child, the son has schizophrenia. And these are the three daughters with relatively, moderately abnormal, and quite abnormal. So an asymptomatic daughter with a father with schizophrenia with an abnormal ratio marries an unsuspecting normal male, and you can see in this family they then produced two children with schizophrenia, with highly abnormal ratios. So again the possibility, like some of the other measures we have talked about, is there may be neuro-physiologic abnormalities in information processing.
Receptors and neurotransmitters; of course, most of the attention has been on dopamine. The evidence really is not very good about abnormalities in dopamine receptors. Norepinephrine also, not much part of it in abnormalities. A lot more interest now in glutamate receptors and I’ll talk about that further tomorrow, but there have been some fairly impressive findings of abnormal glutamate receptor density and composition, particularly in frontal cortex hippocampus. Inconsistent findings of altered serotonin activity. So no strong evidence of abnormal neuro-receptors or transmitters other than possibly new evidence with glutamate. The dopamine hyperactivity model, which you should be aware of it, for no other reason than historically, suggests that schizophrenia is associated with increased activity of dopamine, primarily in the meso-limbic dopamine pathways in the temporal lobes. And possibly decreased dopamine activity in the meso-cortical pathways of the prefrontal cortex.
Evidence for the dopamine model - and this is historically of great significance - dopamine agonist cause psychosis, drugs like amphetamine. All conventional antipsychotics are dopamine antagonists, and the affinity for D2 receptors of antipsychotic drugs correlates with antipsychotic potency. Compelling evidence - it’s only compelling that the treatment of psychosis is based on D2 blockades. Not compelling that it’s primarily an abnormality of dopamine. Some of the evidence against other drugs, like PCP - phencyclidine - which acts on glutamate are possibly better models in schizophrenia. The antipsychotic effect of drugs often occurs after a delay of several weeks. If this was simply a matter of blocking dopamine, you could expect an immediate antipsychotic effect. Again, as I mentioned, there is really no good evidence of dopamine abnormalities.