Upload
dangkhue
View
216
Download
1
Embed Size (px)
Citation preview
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