12. schizophrenia ii

12 01neurLecture 12, Oct 15, 2013Schizophrenia II

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Schizophrenia and drug use As we saw, genetics plays a big role in the

development of schizophrenia. !

However, having schizophrenic genes does not guarantee that you develop the disorder.! There must be something in the environment that can

trigger it.

Marijuana use may be just such a trigger. !

One of the genes that seems to be associated with schizophrenia is called COMT.! Having one or two bad copies of this gene is not

dangerous on its own. But if this gene is combined with adolescent marijuana

use, the risk of schizophrenia more than doubles.


Anatomical basis of schizophrenia Anatomical studies of brains from

people with schizophrenia show enlarged lateral ventricles.!

Ventricle size on its own is not a problem, but since ventricles are empty space, it suggests that nearby parts of the brain either did not develop properly, or have atrophied.!

The empty space left behind fills with CSF.!

It is di" cult to tell whether this observation causes schizophrenia, or if its simply a consequence of the disease.! Genetic studies suggest that enlarged

ventricles are an inherited risk factor, present in both people with schizophrenia and their healthy siblings.

MRI image of healthy and schizophrenic (right) brain. Note the enlarged lateral ventricles in the person with schizophrenia.


Anatomical basis of schizophrenia In addition to gross structural

pathologies, several subtle microscopic pathologies have been characterized.!

Post-mortem brains from people with schizophrenia show reduced dendritic spine density in the prefrontal cortex.! Dendritic spines are small knobs

located on dendrites. Each dendritic spine represents a pre-synaptic terminal. Photomicrograph of Golgi-Cox stained

dendrites. Note the reduced spine density in the dendrite in the right photo (from a patient with schizophrenia).


Anatomical basis of schizophrenia Patients with schizophrenia often show

reductions in the size of the hippocampus. This can be measured in living patients by techniques such as structural MRI.!

! Based on comparisons between young

and old patients, reductions in hippocampal volume are due to degradation. Young patients who are just showing symptoms for the first time have normal sized hippocampi. !

The degree of hippocampal degradation is correlated with illness severity people with worse symptoms have smaller hippocampal volume.!

Post-mortem samples show disorganized neurons in the hippocampus of schizophrenia brains.!

Structural MRI of human brain, showing areas of reduced hippocampal volume.

Illustration from Kolb & Wishaw, An Introduction to Brain and Behavior. Sinauer, 2014


Brain imaging during hallucinations Studies of patients experiencing

auditory hallucinations show that they have increased activation of Wernickes area.! Interestingly, this area is involved in

the interpretation of speech. This might support the idea that

people who are hearing voices are in fact hearing their own thoughts (but cannot recognize them).

Wernickes area is located in the left temporal lobe.


Neurochemical basis While it is valuable to know about the anatomical

correlates of schizophrenia, that knowledge does not help treat the disease.!

Instead, it is important to seek out the neurotransmitter systems that seem to be a#ected by schizophrenia.! This allows for the development of drugs to target

these neurotransmitters, and ideally correct any imbalances.

But where can we start? This is especially di" cult because the symptoms of schizophrenia are di" cult to model fully in lab rats!


Antipsychotic drugs A major advance in the treatment of

schizophrenia came with the discovery of chlorpromazine (trade name: Thorazine) in the early 1950s.!

Chlorpromazine was tried as an anesthetic and for various other purposes, but it produced amazing success when given to psychotic patients.! Patients were said to be ready to return to

normal life, often after years of crippling psychosis.

Because of its e#ects on psychosis, chlorpromazine and related drugs are called antipsychotics.! Chlorpromazine is the first discovered member

of the phenothiazine family of first-generation antipsychotics.

Vintage chlorpromazine (Thorazine) ad. Thorazine was offered as a cure not only for psychosis, but a lso fo r dement ia , nausea, rowdiness, hiccups, menopause, etc.,


Antipsychotic drugs What makes the antipsychotics unique is

that they reduce psychotic symptoms without producing too much general sedation.! Psychotic patients had been sedated for

years, but chlorpromazine relieved them of symptoms without making them hopelessly sleepy

This breakthrough allowed patients to finally leave their institutions and resume normal life.! The deinstitutionalization movement was

kick-started by the discovery of chlorpromazine.

For this reason, the discovery of chlorpromazine was one of the most important breakthroughs in the history of psychiatry.

The number of patients in mental institutions began to decline rapidly following the discovery of chlorpromazine and other similar drugs.



Antipsychotic drugs If antipsychotic drugs like

chlorpromazine can reduce the symptoms of schizophrenia, then learning how they work can help us understand the disorder itself.!

It turns out that chlorpromazine a#ects many neurotransmitter systems, but its e#ects on dopamine are the most important for treating psychosis. !

Chlorpromazine, and all other antipsychotics work primarily by blocking dopamine receptors, specifically the D2 variety.!

Illustration from Barlow & Durand, Abnormal Psychology: An Integrated Approach. Cengage, 2011

Dopamine receptor !

Chlorpromazine ! Dopamine !


Antipsychotic drugs Dopamine D2 receptors are found in a

number of places, but it seems that the striatum is the most important for schizophrenia.! The striatum is part of the basal ganglia.

The positive symptoms of schizophrenia seem to be caused by excessive stimulation of dopamine D2 receptors in the striatum.!

So, blocking dopamine D2 receptors in the striatum with drugs like chlorpromazine relieves the positive, psychotic symptoms of schizophrenia.!

Images of D2 receptor binding in the striatum of a patient with schizophrenia before and after haloperidol treatment (haloperidool is another kind of first-generation antipsychotic).


Further evidence for dopamines role Weve seen how blocking dopamine

receptors improves psychotic symptoms. A great way to expand upon this finding would be to see if excess dopamine stimulation causes psychotic symptoms.!

It turns out that stimulant drugs such as cocaine and amphetamine can, when taken in high doses, produce psychosis in drug users.! As detailed previously, cocaine (and

amphetamine) works by increasing dopamine release in the brain.

So in general, drugs that decrease dopamine signaling reduce psychosis, drugs that increase dopamine signaling cause psychosis. ! This all adds up to some fairly strong evidence

for the role of dopamine in schizophrenia


Dopamine and delusions Dopamine in the striatum is involved in learning and attention, and

this is partly the reason why drug-induced dopamine release teaches addictive behaviors and attention to stimuli related to drug use. ! The formal name for this theory is incentive salience.

Excess dopamine activity in the striatum may cause schizophrenia patients to pay too much attention to irrelevant stimuli.! They also may feel that these stimuli are very important, but for vaguely

defined reasons.

This could explain delusional thinking particularly delusions of reference.!

Dopamine release is increased by stress, and schizophrenia symptoms (particularly delusions) are also increased by stress.!


More about dopamine It turns out that schizophrenia may also

involve under-stimulation of dopamine D1 receptors in the prefrontal cortex.!

This condition is called hypofrontality, and it can explain why people with schizophrenia often struggle with planning, problem solving, and high-level reasoning.!

The ideal drug would be able to block D2 receptors, but activate D1 receptors. Unfortunately, no such drug has been discovered yet.!


Evidence against dopamine Dopamine plays an important role in positive symptoms, but it

cannot be the whole story. !

1. There is only limited evidence that people with schizophrenia produce more dopamine naturally, or that they have more dopamine D2 receptors.!

2. Also, antipsychotic drugs begin blocking dopamine D2 receptors immediately, but symptoms take a lot longer to disappear. !

3. Newer drugs like clozapine work very well, but actually dont block D2 receptors as much as older drugs.!

4. And, some patients simply dont respond to antipsychotic drugs at all.! These tend to be patients with more negative symptoms.


Side effects of antipsychotics While the antipsychotics can often be very

successful in relieving patients of the symptoms of schizophrenia, patient non-compliance is a huge concern.! Estimates show that approximately 40-50% of patients

on antipsychotic medication stop taking them within the first year.

Quitting these drugs can have disastrous e#ects. The full spectrum of schizophrenia symptoms can return after only a few days.! A relapse into psychosis can quickly destroy years

worth of therapy and attempts to build a stable life.

Ideally, patients should be supervised to ensure that they take their medications appropriately.! However, we dont have the resources for this (even in

institutional settings, cheeking pills is common). Moreover, there are ethical concerns with forcing

people to take medications (with the possible exception of violent criminals).

Medicat ions are often given in compliance packaging, reminding patients to take the right pills at the right time (and providing evidence if they skip a dose)>


Side effects of antipsychotics Patients taking on the side e#ects of antipsychotic drugs report:!

Sedation, tiredness, drowsiness Deterioration in the ability to think or concentrate (~18%) Problems with salivation (usually excess) (~16%) Blurred vision (~16%)

On average, about 25% of people have a negative attitude toward these medications (and only about 33% found the drugs beneficial).!

Antipsychotics (particularly newer drugs such as clozapine) can also lead to weight gain, type-II diabetes.! Clozapine also carries the risk of agranulocytosis severely lowered

white blood cell count.

Most troublesome out of all the side e#ects are the ones that a#ect motor function: the extrapyramidal symptoms and tardive dyskinesia.!


Extrapyramidal symptoms Extrapyramidal symptoms resemble the symptoms of

Parkinsons disease. These include:! Muscle rigidity Tremor Masked face Slowing of movements Cogwheel rigidity

They are a risk with all antipsychotics, but they are most common with first-generation antipsychotics (like chlorpromazine) that block the dopamine D2 receptor.!


The extrapyramidal system The extrapyramidal system is

actually not a single system (so no easy diagram). !

It is a system that serves to modulate voluntary and involuntary motor function.!

Extrapyramidal motor pathways involve brainstem structures (pons, medulla) as well as the basal ganglia and cerebellum.!

The extrapyramidal system is much more complicated than the pyramidal system.


The extrapyramidal system The substantia nigra (black substance) is a

midbrain structure that modulates the extrapyramidal motor system.! Parkinsons disease is associated with neural

death in the substantia nigra.

The substantia nigra sends axons that release dopamine into the striatum.!

Dopamine, in this case, is critical for the ability of the extrapyramidal system to control movement.!

Given this, it is not surprising that motor symptoms often appear when dopamine receptors are blocked by antipsychotics.! When blocked, this system cannot do its job,

and a syndrome resembling Parkinsons disease results.

The nigrostriatal pathway is critical for the initiation of movements.



Tardive dyskinesia Sometimes patients on long-term antipsychotic treatment develop

tardive dyskinesia. This syndrome comes on slowly (hence tardive) after years of treatment.!

Tardive dyskinesia is characterized by repeated, involuntary movements.! Odd facial expressions Lip smacking Tongue protrusion Involuntary movement of limbs

Unlike the previous extrapyramidal symptoms, tardive dyskinesia may involve hypersensitivity to dopamine in the striatum.! This may be a compensatory response to blocking dopamine receptors in

the striatum.

Tardive dyskinesia is often mistaken for a mental illness in and of itself.!


Tardive dyskinesia

http://www.youtube.com/watch?v=t_NKRS8lLWA!


But wait, theres glutamate! Cocaine and amphetamine are not the only

drugs capable of causing psychosis. Phencyclidine (PCP), also known as angel dust can also induce psychosis.! PCP mimics the positive symptoms of

schizophrenia. PCP has a stronger effect in people diagnosed

with schizophrenia.

PCP blocks a kind of glutamate receptor called the NMDA receptor.!

The NMDA receptor is widely expressed in the brain, and may play a role in schizophrenia.!


The role of NMDA receptors If blocking the NMDA receptor produces schizophrenia-like

symptoms, what does the receptor normally do?!

The NMDA receptor is involved in:! Brain development Learning & memory Cognition Regulating dopamine release!

People with schizophrenia have a too few NMDA receptors, or some other problem with their NMDA receptors.! This could explain the cognitive, negative, and positive symptoms of

schizophrenia, as well as the dopamine effects described earlier.

For this reason, drugs that help activate the NMDA receptor may be useful treatments for schizophrenia. ! Gycline and D-serine are amino acid based therapies. Drugs that inhibit breakdown of glycine in the brain may also help.


Quiz time!

What neurotransmitter is the ligand for the NMDA receptor? In other words, what neurotransmitter binds to the NMDA receptor?$!

1. Glutamate!2. NMDA!3. GABA!4. Dopamine!

12. schizophrenia ii

Documents

risk of schizophrenia

development of schizophrenia

schizophrenia iineur

young patients

enlarged ventricles

old patients

brain imaging

living patients