Lecture 12, Oct 15, 2013

n e u r1
2 0
1

Schizophrenia II

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

NEUR%1201%%Fall%2013%%Harry%MacKay%

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 dicult 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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

Structural MRI of human brain, showing

areas of reduced hippocampal volume.

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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
aected 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 dicult

because the symptoms of schizophrenia are
dicult to model fully in lab rats

NEUR%1201%%Fall%2013%%Harry%MacKay%

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 eects on psychosis,

chlorpromazine and related drugs are called
antipsychotics.
Chlorpromazine is the first discovered member
of the phenothiazine family of first-generation
antipsychotics.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Vintage chlorpromazine (Thorazine)

ad. Thorazine was offered as a
cure not only for psychosis, but
also for dementia, 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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

The number of patients in mental institutions

began to decline rapidly following the
discovery of chlorpromazine and other similar
drugs.

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

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.

Chlorpromazine!

Dopamine!

It turns out that chlorpromazine

aects many neurotransmitter
systems, but its eects on
dopamine are the most important
for treating psychosis.
Chlorpromazine, and all other
antipsychotics work primarily by
blocking dopamine receptors,
specifically the D2 variety.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Dopamine receptor!

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

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Side eects 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 eects.

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).

NEUR%1201%%Fall%2013%%Harry%MacKay%

Medications 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 eects of antipsychotics

Patients taking on the side eects 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 eects are the ones that aect
motor function: the extrapyramidal symptoms and tardive
dyskinesia.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

The nigrostriatal pathway is critical for the

initiation of movements.

When blocked, this system cannot do its job,

and a syndrome resembling Parkinsons
disease results.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Tardive dyskinesia

http://www.youtube.com/watch?v=t_NKRS8lLWA
NEUR%1201%%Fall%2013%%Harry%MacKay%

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.

NEUR%1201%%Fall%2013%%Harry%MacKay%

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.
NEUR%1201%%Fall%2013%%Harry%MacKay%

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

NEUR%1201%%Fall%2013%%Harry%MacKay%