Psychotic Disorders and their Treatment

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Alicia Fitzgerald
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1 Psychotic Disorders and their Treatment Bruce M. Cohen, M.D., Ph.D. Director, Stanley Research Center, McLean Hospital Professor of Psychiatry, Harvard Medical School MIT 69

2 Psychotic disorders are characterized by substantial 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

3 While there are many causes of psychosis, most of our patients are classified as having either: schizophrenia, typified by a chronic course and more complex delusions and hallucinations or bipolar disorder, typified by a recurrent course and extremes of mood.

4 However, it may be incorrect to think of bipolar disorder and schizophrenia as either distinct or homogeneous disorders. Many factors may interact to produce a range of conditions with various features of the syndromes of bipolar disorder and schizophrenia.

5 Genetics The inheritance of risk for psychotic disorders appears best to fit a model including multiple, interacting genes. We are collaborating with the Broad Institute to identify such genes, but at present no common risk genes are well documented.

6 Brain Imaging Subtle changes in the brain, especially in areas associated with complex thinking and emotion, can be seen in bipolar disorder and schizophrenia.

7 Examples of MR Findings in Schizophrenia, Bipolar Disorder and Major Depression Bipolar Major Schizophrenia Disorder Depression MRI VBR Cerebellum Hippocampus MRS NAA Lac, Glx β-ntp (Temporal Lobe) (Gray Matter) (Basal Ganglia) fmr PFC Amygdala Anterior Cingulate

8 Activity in the Right Medial Dorsal Thalamus during a Verbal Fluency Task in Healthy Controls and Patients with Schizophrenia Mean Signal Intensity Time (sec) Controls Mean Signal Intensity Patients Time (sec) Cohen and Yurgelun-Todd

9 Cerebral Blood Volume Changes in the Thalamic Region After Risperidone Treatment Thalamus Placebo Risperidone Cohen and Yurgelun-Todd

10 Treatment of Psychosis Currently available antipsychotic and mood stabilizing medications are effective but work slowly, produce many side effects and often achieve only partial symptom relief.

11 General Overview of Components of the McLean Stanley Center The Stanley Research Center at McLean Hospital supports a multidisciplinary team of basic and clinical scientists devoted to discovering new treatments for bipolar disorder, schizophrenia and related illnesses. Techniques and discoveries arise from clinical, laboratory and brain imaging components.

12 Why are treatment studies relevant to studies of cognition and brain functioning? Medication and other treatment trials provide an opportunity to study subjects when they are more and less symptomatic The effects of medication can clarify the mechanism by which the brain processes information in health and illness

13 Stanley Research Center at McLean Major Preclinical Projects Kappa agents Low Field Magnetic Stimulation (LFMS) Trace amine modulators Neuroregenerative agents Bone marrow derived stem cells Stress reducing agents to prevent relapse

14 Stanley Research Center at McLean Current Clinical Trials Kappa agonists in mania Secretin D-Serine Omega 3 fatty acids plus cytidine Taurine in mania SAMe for bipolar depression Low field magnetic stimulation MR Biofeedback

15 One Example of our Research on New Treatments Research by McLean investigators suggests that kappa receptor agonists, antagonists and partial agonists may have antimanic, antidepressant and mood stabilizing effects.

16 Increasing CREB Reduces the Effects of Antidepressants in Rats Kappa receptor dynorphin P P CREB CREB altered gene expression Carlezon et al Blocking kappa receptors mimics the effects of antidepressants in rats

17 Dynorphin may also be important in mediating the effects of antipsychotic/antimanic drugs.

Nucleus Accumbens Clozapine Treated Rat GFAP

indicates that cells responding to antipsychotic

Combined red and green staining to produce yellow

18 Nucleus Accumbens Clozapine Treated Rat GFAP Dynorphin VAChT Separate red and green staining indicates that cells responding to antipsychotic drugs are not glia (GFAP) or cholinergic (VAChT). Combined red and green staining to produce yellow indicates that activated cells are dynorphinergic neurons. Ma et al., 2003

19 Unlike current medications, agents acting at kappa receptors may have rapid effects on mania and depression No currently available drugs are specific kappa receptor modulators We are synthesizing kappa specific agents and testing available drugs in the meantime

20 H N CH 2 CH C(CH 3 ) 2 C CH 3 HO H CH 3 (+/-) Pentazocine Hydrochloride Action at Opiate Receptors kappa (κ) mu (µ) delta (δ) sigma (σ) nearly full mostly weak partial agonist antagonist agonist agonist

21 Pentazocine Induced Change in Acute Mania or Sedation Symptom Score Less More Score 35 Sedation Mania Baseline 1 Hour 2 Hour 3 Hours 4 Hours 5 Hours (Pentazocine) (Pentazocine) in 10 subjects

Schizophrenia. Psychology 372 Physiological Psychology. Overview. Characterized by. Disorganized Thoughts Hallucinations Delusions Bizarre behaviors

Schizophrenia. Psychology 372 Physiological Psychology. Overview. Characterized by. Disorganized Thoughts Hallucinations Delusions Bizarre behaviors Overview Schizophrenia Psychology 372 Physiological Psychology Steven E. Meier, Ph.D. Listen to the audio lecture while viewing these slides Probably consists of more than one disorder Is the most devastating