Psychotic Disordersand their Treatment

Bruce M. Cohen, M.D., Ph.D.

Director, Stanley Research Center, McLean HospitalProfessor of Psychiatry, Harvard Medical School

MIT ‘69

Psychotic disorders are characterized bysubstantial abnormalities of thought,

perception, mood and behavior:

• Delusions (odd and erroneous beliefs)

• Hallucinations (False sensory percepts)

• Disorganized/illogical thinking and speech

• Odd, inappropriate or disorganized behavior

• Inappropriate or extreme mood and affect

While there are many causes of psychosis,most of our patients are classified as having

either:

schizophrenia, typified by a chronic course andmore complex delusions and hallucinations

orbipolar disorder, typified by a recurrent

course and extremes of mood.

However, it may be incorrect to think ofbipolar disorder and schizophrenia as

either distinct or homogeneous disorders.

Many factors may interact to producea range of conditions with various

features of the syndromes ofbipolar disorder and schizophrenia.

Genetics

The inheritance of risk for psychotic disordersappears best to fit a model including multiple,interacting genes.

We are collaborating with the Broad Instituteto identify such genes, but at present nocommon risk genes are well documented.

Subtle changes in the brain, especiallyin areas associated with complex

thinking and emotion, can be seen inbipolar disorder and schizophrenia.

Brain Imaging

Bipolar MajorSchizophrenia Disorder Depression

MRI ↑ VBR ↓ Cerebellum ↓ Hippocampus

MRS ↓ NAA ↑ Lac, Glx ↓ β-NTP(Temporal Lobe) (Gray Matter) (Basal Ganglia)

fMR ↓ PFC ↑ Amygdala ↓ Anterior Cingulate

Examples of MR Findings in Schizophrenia,Bipolar Disorder and Major Depression

Activity in the Right Medial Dorsal Thalamusduring a Verbal Fluency Task in HealthyControls and Patients with Schizophrenia

0.985

0.995

1.005

1.015

1.025

3 21 39 57 75 93 111 129 147Time (sec)

Mea

n Si

gnal

Inte

nsity

Controls

0.985

0.995

1.005

1.015

1.025

3 21 39 57 75 93 111 129 147Time (sec)

Mea

n Si

gnal

Inte

nsity

Patients

Cohen and Yurgelun-Todd

Thalamus Placebo Risperidone

Cerebral Blood Volume Changes in the Thalamic RegionAfter Risperidone Treatment

Cohen and Yurgelun-Todd

Currently available antipsychoticand mood stabilizing medications are

effective but work slowly,produce many side effects and

often achieve only partial symptom relief.

Treatment of Psychosis

The Stanley Research Center at McLeanHospital supports a multidisciplinary teamof basic and clinical scientists devoted todiscovering new treatments for bipolardisorder, schizophrenia and related illnesses.Techniques and discoveries arise fromclinical, laboratory and brain imagingcomponents.

General Overview of Componentsof the McLean Stanley Center

• Medication and other treatment trialsprovide an opportunity to study subjectswhen they are more and less symptomatic

• The effects of medication can clarify themechanism by which the brain processesinformation in health and illness

Why are treatment studies relevant tostudies of cognition and brain functioning?

Kappa agentsLow Field Magnetic Stimulation (LFMS)Trace amine modulatorsNeuroregenerative agentsBone marrow derived stem cellsStress reducing agents to prevent relapse

Stanley Research Center at McLeanMajor Preclinical Projects

Kappa agonists in mania SecretinD-SerineOmega 3 fatty acids plus cytidineTaurine in maniaSAMe for bipolar depressionLow field magnetic stimulationMR Biofeedback

Stanley Research Center at McLeanCurrent Clinical Trials

Research by McLean investigatorssuggests that kappa receptor agonists,

antagonists and partial agonistsmay have antimanic, antidepressant

and mood stabilizing effects.

One Example of our Researchon New Treatments

Increasing CREBReduces the Effects ofAntidepressants in Rats

Blocking kappa receptorsmimics the effects ofantidepressants in rats

CREB

P

P

alteredgeneexpression

dynorphin

Kappareceptor

CREB

Carlezon et al

Dynorphin may also be important inmediating the effects of

antipsychotic/antimanic drugs.

GFAP Dynorphin VAChT

Nucleus Accumbens Clozapine Treated Rat

Separate red and green staining indicates that cells responding to antipsychoticdrugs are not glia (GFAP) or cholinergic (VAChT).

Combined red and green staining to produce yellow indicates that activatedcells are dynorphinergic neurons.

Ma et al., 2003

• Unlike current medications, agentsacting at kappa receptors may haverapid effects on mania and depression

• No currently available drugs are specifickappa receptor modulators

• We are synthesizing kappa specificagents and testing available drugs in themeantime

(+/-) Pentazocine Hydrochloride

CH3

C CH3

H

NCH2CH C(CH3)2

H

HO

Action at Opiate Receptors

kappa (κ) mu (µ) delta (δ) sigma (σ)

nearly full mostly weak partial agonist antagonist agonist agonist

Pentazocine Induced Change inAcute Mania or Sedation Symptom Score

0

5

10

15

Baseline(Pentazocine)

1 Hour 2 Hour(Pentazocine)

3 Hours 4 Hours 5 Hours

Less

M

ore

20

25

30

35 SedationMania

Baseline

Sco

re

in 10 subjects