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Learning Where Psychiatric Illness "Lives:" Brain Regions Involved in Mood and Psychotic Disorders

Daniel Healy, M.D. Learning Where Psychiatric Illness "Lives:" Brain Regions Involved in Mood and Psychotic Disorders. Major Categories. Psychotic Disorders Schizophrenia Schizoaffective Disorder Mood Disorders Major Depressive Disorder + psychosis

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Learning Where Psychiatric Illness "Lives:" Brain Regions Involved in Mood and Psychotic Disorders

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  1. Daniel Healy, M.D. Learning Where Psychiatric Illness "Lives:" Brain Regions Involved in Mood and Psychotic Disorders

  2. Major Categories • Psychotic Disorders • Schizophrenia • Schizoaffective Disorder • Mood Disorders • Major Depressive Disorder + psychosis • Bipolar Disorder (Manic-Depression) + psychosis • Anxiety Disorders • PTSD • OCD • GAD • Panic Disorder • Personality Disorders • Cluster A (Paranoid, Schizoid, Schizotypal • Cluster B (Borderline, Antisocial, Narcissiistic, Histrionic) • Cluster C (Avoidant, Dependent, Obsessive –Compulsive) • Substance Abuse Disorders

  3. Neuroanatomy • Problem in certain brain regions that comprise circuits • Frontal lobe- cognition, alertness, control impulses, motivation • Temporal lobe (hippocampus plus)-forming memories, auditory hallucinations • Thalamus-interprets inputs from the five senses • Cingulategyrus-normal expression of emotions • Caudate-putamen, nucleus accumbens-fine tunes emotions and movements, reward/reinforcement • Parietal lobe-allows you to be aware of your own actions • Amygdala-anxiety, anger • Hypothalamus-sleeping, eating

  4. Neurotransmitters • Problem with certain neurotransmitters (nerves don’t connect, gap is called synapse, neurotransmitters “connect” nerves) • Dopamine-reward/reinforcement, paranoia, substance abuse • Glutamate-ubiquitous, excitatory, too much kills neurons, stress increases cortisol increases glutamate (stress kills nerves), cognition, pain/temperature, affects dopamine release • Serotonin-depression, anxiety, abnormal movements • GABA-ubiquitous, inhibitory, anxiety, cognition • Acetylcholine-memory, cognition, movements, nicotine affects acetylcholine nerves • http://www.brainexplorer.orgis a good website; so is www.sharpbrains.com, which puts brain function in the context of investing.

  5. Neurochemical anatomy • Why it is complicated • Billions of connections • Different brain areas use different neurotransmitters • Neurotransmitters have multiple types of receptors, some having opposite effects for same neurotransmitter • Few medications affect only one neurotransmitter, so can’t control the (side) effects of medications (most selective, least effective) • Homeostasis, tendency to maintain status quo, means that it is hard to drive one area only • Giving a medication to affect one area causes changes in other regions • Genes and environment are both influential

  6. Psychosis • Defined by impaired reality testing • Positive symptoms (presence of abnormality): • thought content: delusions • perception: hallucinations • thought stream: grossly disorganized • behavior: grossly disorganized Dopamine imbalance in the frontal lobe and caudate putamen)

  7. Psychosis • Negative symptoms (absence of normality): • Affect blunted or flat • Avolition/amotivation • Alogia: decreased amount or content • Anhedonia: lack of interests Dopamine and glutamate imbalance (too little frontal lobe, too much in caudate putamen, maybe amygdala and hippocampus)

  8. Attention / Arousal Modelof Schizophrenia • Stimulus flooding • Lack of an effective filter • Too much information from the environment • Leads to withdrawal from social contact • Stimulus overload • Leads to frustration, poor concentration, nervousness Thalamus uses gaba and glutamate to filter info from all five senses

  9. First Generation Antipsychotics • Chlorpromazine Thorazine • FluphenazineProlixin • Haloperidol Haldol • LoxapineLoxitane • MesoridazineSerentil • MolindoneMoban • PerphenazineTrilafon • PimozideOrap • ThioridazineMellaril • ThiothixeneNavane • TrifluoperazineStelazine

  10. Long Acting First Generation Antipsychotics • Haloperidol Decanoate (Haldol) • FluphenazineDecanoate (Prolixin)

  11. Benefits of First Generation Antipsychotics • Effective control of psychotic symptoms in responsive patients • Reduced need for institutional care • Clinical experience • Relatively inexpensive, generics available

  12. Limitations of First Generation Antipsychotics • Lack of efficacy • Negative symptoms (frontal lobe, glutamate) • Depression • Safety and tolerability concerns • Extrapyramidal symptoms / tardive dyskinesia (dopamine/acetylcholine in caudate putamen) • Sedation (frontal lobe) • Cognitive impairments (frontal lobe) • Prolactin elevation (dopamine pituitary) • Cardiovascular symptoms (arrhythmias) • Nonadherence

  13. Second Generation Antipsychotics • clozapine (Clozaril) 1990 • risperidone (Risperdal) 1994 • olanzapine (Zyprexa) 1996 • quetiapine (Seroquel) 1997 • ziprasidone (Geodon) 2001 • aripiprazole (Abilify) 2002 • paliperidone (Invega) 2006 • ileoperidone (Fanapt) 2009 • asenapine (Saphris) 2009 • lurasidone (Latuda) 2011

  14. Dissolvable Second Generation Antipsychotics • clozapine (Fazaclo) • risperidone (Risperdal M-tabs) • olanzapine (ZyprexaZydis) • aripiprazole (AbilifyDiscmelt) • asenapine (Saphris is sublingual)

  15. Long Acting Second Generation Antipsychotics • risperidoneConsta (Risperdal) • paliperidoneSustenna (Invega) • olanzapineRelprevv (Zyprexa) (Watch out for coma. Seriously.)

  16. The Benefits of Second Generation Antipsychotics • At least as effective as conventional agents • Shift the risk / benefit ratio • The EPS advantage (serotonin) • Reduced risk of tardive dyskinesia (dopamine serotonin) • Broader symptom efficacy • May enhance compliance, reduce hospitalizations, be cost-effective • Challenge providers to deliver effective rehabilitation services

  17. The Limitations of Second Generation Antipsychotics • Expensive • Weight gain, diabetes, cholesterol • Sedating (histamine) • Sometimes not efficacious against positive symptoms (dopamine) • Seroquel can be a drug of abuse

  18. Increased Morbidity and Mortality in Schizophrenia • Life expectancy increasing in general population (when controlling for infant mortality) • Life expectancy still around 55 for folks diagnosed with schizophrenia • Lifestyle improvements not adopted by the people we serve (exercise, nutrition, smoking) • Access to healthcare • Weight gain from medications

  19. Major Depression: Emotional Symptoms • Sad, irritable or empty mood • Diurnal variation • Diminished capacity for enjoyment • Diminished interests • Frontal lobe, serotonin, norepinephrine, dopamine (anhedonia)

  20. Major Depression:Thought (Cognitive) Symptoms • Difficulty concentrating • Indecisiveness • Memory problems • Depressed content of thought • Worthlessness • Guilt • Hopelessness • Death and Suicide Frontal lobe, serotonin, norepinephrine

  21. Major Depression:Somatic Symptoms (Body Functions) • Sleep disturbances • Appetite disturbances, weight changes • Fatigue, low energy • Upset stomach, constipation • Physical pain • Hypothalamus serotonin, norepinephrine, histamine (sleep)

  22. Major Depression: Severity • Mild to severe • May include psychosis, poor self care, suicide • Abraham Lincoln describing his own depression: • “I am now the most miserable man living. If what I feel were equally distributed to the whole human family, there would not be one cheerful face on earth. Whether I shall ever be better, I cannot tell. I awfully forebode I shall not. To remain as I am is impossible. I must die or be better, it appears to me.”

  23. Antidepressant Medications • All antidepressants must be taken for at least 4-6 weeks to have substantial benefit • Studies are showing that if you don’t respond in the first week or two, you’re probably not going to, so augment or change earlier than previously recommended.

  24. Neuroanatomy • Problem in certain brain regions that comprise circuits • Frontal lobe- mood, cognition, alertness, motivation • Cingulategyrus-normal expression of emotions • Caudate-putamen-fine tunes emotions and movements • Amygdala-anxiety, anger • Hypothalamus-sleeping, eating • Hippocampus-memory

  25. Neurotransmitters • Dopamine-reward/reinforcement, anhedonia • Glutamate-ubiquitous, excitatory, too much kills neurons, stress increases cortisol increases glutamate (stress kills nerves), cognition, affects dopamine release • Serotonin- all aspects of depression • Norepinephrine- all aspects of depression • GABA-ubiquitous, inhibitory, anxiety, cognition • Acetylcholine-memory, cognition,

  26. Antidepressants: Selective SerotoninRe-uptake Inhibitors (SSRIs) • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • Citalopram (Celexa) • Escitalopram (Lexapro) • Fluvoxamine (Luvox)

  27. Common Side Effects of SSRIs • Nausea • Dry mouth • Diarrhea or stomach upset • Lack of appetite • Feeling tired, weak, or dizzy • Headache • Anxiety or nervousness • Sexual dysfunction

  28. “Atypical” Antidepressants • Bupropion (Wellbutrin, Zyban) • Can cause agitation, anxiety, insomnia • Venlafaxine (Effexor, Pristiq) • Hypertension, SSRI-like side effects • Trazodone (Desyrel) • Sedation, dizziness • Nefazodone (Serzone) • SSRI-like but more sedation, monitor for liver toxicity • Mirtazapine (Remeron) • May cause sedation, weight gain • Duloxetine (Cymbalta) • May cause nausea

  29. Tricyclic Antidepressants (TCAs) • Amitriptyline (Elavil) • Clomipramine (Anafranil) • Desipramine (Norpramin) • Doxepin (Sinequan) • Imipramine (Tofranil) • Nortriptyline (Pamelor)

  30. TCA Side Effects • Can be fatal in overdose • Fatigue, sedation • Light-headedness, dizziness • Dry mouth • Constipation • Weight gain • Headache

  31. Antidepressants: Monoamine Oxidase Inhibitors (MAOIs) • Isocarboxazid (Marplan) • Meclobemide (Aurorix) • Phenelzine (Nardil) • Tranylcypromine (Parnate) • Selegiline (Eldepryl)

  32. MAOI Challenges • Strict dietary restriction • Avoid aged cheeses and meats, soy sauce, soy beans, fava beans, wine, beer, others • Avoid other anti-depressants • Avoid over-the-counter medications

  33. Side Effects of MAOIs • Hypertensive crisis • Serotonin syndrome • Weight gain • Fatigue • Constipation • Dizziness

  34. Bipolar Disorder: The Course • 1% of general population • Equal in men and women • Age of onset similar to schizophrenia • Episodes can come on very fast (1-7 days) • Later episodes longer, more severe, more frequent • Substance abuse common • Heredity plays a greater role than in depression • Family members also at higher risk for major depression • High suicide risk

  35. Mania: Signs and Symptoms • Persistently elevated, expansive or irritable mood for one week • Associated symptoms (need 3 or more for diagnosis) • Inflated self -esteem or grandiosity • Decreased need for sleep • More talkative • Racing thoughts or flight of ideas • Distractibility • Agitation or increase in activities • Excessive involvement in pleasurable activities with a high risk for painful consequences • Spending sprees, sexual indiscretions, foolish investments

  36. Hypomania • Distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days plus three of the following: • inflated self-esteem or grandiosity • decreased need for sleep (e.g., feels rested after only 3 hours of sleep) • more talkative than usual or pressure to keep talking • flight of ideas or subjective experience that thoughts are racing • distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli) • increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation • excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

  37. Mixed Episode • The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. • B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. • C. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).

  38. Mania Physiology • Frontal lobe and amygdala-emotion regulation • Impulsivity-dopamine reward/reinforcement • Lack of need for sleep-histamine • Increased neuronal firing, glutamate • Mood stabilizers may reduce the chemicals produced after a nerve fires

  39. Mood Stabilizing Medications • FDA Approved Agents • lithium (Eskalith, Lithobid) (mania, depression) • valproate(Depakote) (mania) • carbamazepine XR (Tegretol XR) (mania) • aripiprazole (Abilify) (mania) • asenapine (Saphris) (mania) • chlorpromazine (Thorazine) (mania) • olanzapine(Zyprexa) (mania) • olanzapine + fluoxetine (depression) • lamotrigine(Lamictal) (depression prevention) • risperidone(Risperdal) (mania) • quetiapine(Seroquel) (depression, mania) • ziprasidone (Geodon) (mania)

  40. Lithium • Toxic in overdose • Severe tremor, confusion, disorientation, seizure, coma • Can check blood levels • Tremor • Gastrointestinal symptoms • Increased weight

  41. Depakote • Monitor blood levels • Stomach upset • Weight gain • Sedation • Liver failure • Yellowing of skin or eyes, dark urine, nausea/vomiting • Pancreatitis • Abdominal pain, nausea/vomiting, decreased appetite • Polycystic Ovary risk • Hair loss

  42. Other Mood Stabilizing Medications • Other anticonvulsants • Oxcarbazepine(Trileptal) • Topiramate (Topamax) • Tiagabine (Gabitril) • Gabapentin (Neurontin) • Other second generation antipsychotics • iloperidone (Fanapt) • Conventional neuroleptics • Benzodiazapines

  43. Anxiety Disorders • Posttraumatic Stress Disorder • Obsessive Compulsive Disorder • Generalized Anxiety Disorder • Panic Disorder with or without agoraphobia

  44. Anxiety Disorders • SSRIs, SNRIs, TCAs effective in concert with psychotherapy • Amygdala mediates fear and anxiety, GABA+glutamate balance, norepinephrine, dopamine, serotonin • Frontal lobe mediates increased attention/vigilance, norepinephrine • Hypothalamus-blood pressure, increased heart rate

  45. Antidepressants: Selective SerotoninRe-uptake Inhibitors (SSRIs) • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • Citalopram (Celexa) • Escitalopram (Lexapro) • Fluvoxamine (Luvox)

  46. “Atypical” Antidepressants • Bupropion (Wellbutrin, Zyban) • Can cause agitation, anxiety, insomnia • Venlafaxine (Effexor, Pristiq) • Hypertension, SSRI-like side effects • Trazodone (Desyrel) • Sedation, dizziness • Nefazodone (Serzone) • SSRI-like but more sedation, monitor for liver toxicity • Mirtazapine (Remeron) • May cause sedation, weight gain • Duloxetine (Cymbalta) • May cause nausea

  47. Anxiolytics / Hypnotics • Alprazolam (Xanax) • Chlordiazepoxide (Librium) • Clonazepam (Klonopin) • Diazepam (Valium) • Lorazepam (Ativan) • Oxazepam (Serax) • Temazepam (Restoril) • Triazolam (Halcion) • Zolpidem (Ambien) • Zaleplon (Sonata) Note: all have addiction potential, last four mostly for sleep, GABA in amygdala a major target

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