1. Daniel Healy, M.D.

2.  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

6.  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  Cingulate gyrus-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

7.  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.org is a good website; so is  http://www.brainexplorer.org is a good website; so is www.sharpbrains.com, which puts brain function in the context of investing. http://www.brainexplorer.org www.sharpbrains.com

8.  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

9.  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)

10.  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)

11.  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

12.  ChlorpromazineThorazine  FluphenazineProlixin  HaloperidolHaldol  LoxapineLoxitane  MesoridazineSerentil  MolindoneMoban  PerphenazineTrilafon  PimozideOrap  ThioridazineMellaril  ThiothixeneNavane  TrifluoperazineStelazine

13.  Haloperidol Decanoate (Haldol)  Fluphenazine Decanoate (Prolixin)

14.  Effective control of psychotic symptoms in responsive patients  Reduced need for institutional care  Clinical experience  Relatively inexpensive, generics available

15.  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

16.  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

17.  clozapine (Fazaclo)  risperidone (Risperdal M-tabs)  olanzapine (Zyprexa Zydis)  aripiprazole (Abilify Discmelt)  asenapine (Saphris is sublingual)

18.  risperidone Consta (Risperdal)  paliperidone Sustenna (Invega)  olanzapine Relprevv (Zyprexa) (Watch out for coma. Seriously.)

19.  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

20.  Expensive  Weight gain, diabetes, cholesterol  Sedating (histamine)  Sometimes not efficacious against positive symptoms (dopamine)  Seroquel can be a drug of abuse

21.  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

22.  Sad, irritable or empty mood  Diurnal variation  Diminished capacity for enjoyment  Diminished interests  Frontal lobe, serotonin, norepinephrine, dopamine (anhedonia)

23.  Difficulty concentrating  Indecisiveness  Memory problems  Depressed content of thought  Worthlessness  Guilt  Hopelessness  Death and Suicide Frontal lobe, serotonin, norepinephrine

24.  Sleep disturbances  Appetite disturbances, weight changes  Fatigue, low energy  Upset stomach, constipation  Physical pain  Hypothalamus serotonin, norepinephrine, histamine (sleep)

25.  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.”

26.  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.

27.  Problem in certain brain regions that comprise circuits  Frontal lobe- mood, cognition, alertness, motivation  Cingulate gyrus-normal expression of emotions  Caudate-putamen-fine tunes emotions and movements  Amygdala-anxiety, anger  Hypothalamus-sleeping, eating  Hippocampus-memory

28.  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,

29.  Fluoxetine (Prozac)  Sertraline (Zoloft)  Paroxetine (Paxil)  Citalopram (Celexa)  Escitalopram (Lexapro)  Fluvoxamine (Luvox)

30.  Nausea  Dry mouth  Diarrhea or stomach upset  Lack of appetite  Feeling tired, weak, or dizzy  Headache  Anxiety or nervousness  Sexual dysfunction

31.  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

32.  Amitriptyline (Elavil)  Clomipramine (Anafranil)  Desipramine (Norpramin)  Doxepin (Sinequan)  Imipramine (Tofranil)  Nortriptyline (Pamelor)

33.  Can be fatal in overdose  Fatigue, sedation  Light-headedness, dizziness  Dry mouth  Constipation  Weight gain  Headache

34.  Isocarboxazid (Marplan)  Meclobemide (Aurorix)  Phenelzine (Nardil)  Tranylcypromine (Parnate)  Selegiline (Eldepryl)

35.  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

36.  Hypertensive crisis  Serotonin syndrome  Weight gain  Fatigue  Constipation  Dizziness

37.  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

38.  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

39.  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)

40.  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).

41.  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

42.  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)

43.  Toxic in overdose  Severe tremor, confusion, disorientation, seizure, coma  Can check blood levels  Tremor  Gastrointestinal symptoms  Increased weight

44.  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

45.  Other anticonvulsants  Oxcarbazepine (Trileptal)  Topiramate (Topamax)  Tiagabine (Gabitril)  Gabapentin (Neurontin)  Other second generation antipsychotics  iloperidone (Fanapt)  Conventional neuroleptics  Benzodiazapines

46.  Posttraumatic Stress Disorder  Obsessive Compulsive Disorder  Generalized Anxiety Disorder  Panic Disorder with or without agoraphobia

47.  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

48.  Fluoxetine (Prozac)  Sertraline (Zoloft)  Paroxetine (Paxil)  Citalopram (Celexa)  Escitalopram (Lexapro)  Fluvoxamine (Luvox)

49.  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

50.  Alprazolam (Xanax)  Chlordiazepoxide (Librium)  Clonazepam (Klonopin)  Diazepam (Valium)  Lorazepam (Ativan)  Oxazepam (Serax)  Temazepam (Restoril)  Triazolam (Halcion)  Zolpidem (Ambien)  Zaleplon (Sonata) 50 Note: all have addiction potential, last four mostly for sleep, GABA in amygdala a major target

51.  Sedation  Addiction potential  Can be fatal in overdose, especially if combined with alcohol  Studies show most likely outcome for adding a benzo is to create benzo dependence; either no benefit or trigger for abusing other substances 51

52.  Severe craving lengthens tapering off period  Taking benzos decreases craving for benzos, alcohol, or other substance of abuse, but does not improve illness  Folks with bipolar disorder and depression have a very high risk of developing benzo abuse/dependence, with no evidence that benzos beneficial for mood 52

53.  Many states are restricting or eliminating benzos from formulary  Time-limited, supervised use for detox/withdrawal and akasthisia now only acceptable use for benzos 53

54.  Intending to use the substance  Hoping not to get in trouble  Make bad choices  Do get in trouble  Outcome goal- abstinence or non-harmful use  Dopamine in nucleus accumbens, amygdala frontal lobe, temporal lobe (withdrawal balance of GABA and glutamate) 54

55.  Achieve abstinence before treating mood, anxiety or psychotic disorder 55

56.  Psychotropic medications reduced the likelihood of sobriety 56

57.  No medications available to facilitate sobriety (Antabuse-no data on sobriety) 57

58.  Treat all illnesses simultaneously, and combine medications designed to enhance sobriety with psychosocial interventions 58

59.  Harm reduction is a useful treatment goal as part of the treatment plan. 59

60.  Comorbidity is the expectation, not the exception  Persons diagnosed with schizophrenia  47% use substances  55% of those in psychiatric treatment  Bipolar disorder  62% have substance use disorder  Bipolar consumers more likely to abuse alcohol and cannabis than MDD  Major Depressive disorder  More likely to have alcohol dependence than abuse  Consumers with mood disorders, in general, are likely to abuse benzodiazepines. 60

61.  Provision for basic needs  Assertive community treatment (ACT)  Patient and family psychoeducation  Vocational rehabilitation  Clubhouses  Social skills training  Support groups 61

62.  Motivational enhancement therapy  Cognitive behavioral (relapse prevention)  12 step programs  Contingency management  Family interventions  Self-help manuals/workbooks  Case management 62

63.  There is little evidence that there is a gene that increases likelihood that you will have a co- occurring disorder  There is also little evidence that any one factor “causes” you to develop co-occurring disorder (e.g. personality disorder, “addictive personality”). 63

64.  There is little agreement whether mood disorder symptoms precede or follow substance abuse 64

65.  NO (most of the time)  Treat both conditions simultaneously  Yearly schizophrenia relapse rate  With medication - 15-20%  Without medication - 70%  Without medication and with precipitant such as substance abuse – greater than 70% 65

66.  With deinstitutionalization, more choices including self- determination  Not just to self-medicate symptoms  Relieves feelings of isolation, loneliness, boredom and despair  Facilitates peer interaction and social engagement  Promotes a sense of well-being, escape from life perceived as bleak or hopeless, mitigates withdrawal  Harder to modify behavior if have cognitive impairments  Increases metabolism, effectively reducing doses of medications 66

67.  disulfiram (Antabuse)  Works by interfering with alcohol metabolism- cousin of formaldehyde accumulates in blood, causing illness  Doesn’t affect craving directly, limited data on relapse reduction  More of an aversive treatment  Avoid alcohol in any form (aftershave, etc) 67

68.  naltrexone (Revia)  Works by affecting endogenous opioid system  Reduces craving  Will induce withdrawal if consumer using or abusing opiates  Can’t use opiates for pain management 68

69.  injectible naltrexone (Vivitrol)  Works by affecting endogenous opioid system  Reduces craving  Will induce withdrawal if consumer using or abusing opiates  Can’t use opiates for pain management 69

70.  acamprosate (Campral)  Works by affecting glutamate and/or GABA receptors  May reduce craving by mitigating early withdrawal, and reduces relapse rates  Avoid if consumer has kidney problems 70

71.  methadone (Dolophine)  Works by occupying opiate receptors in same way morphine and its cousins do  Will reduce withdrawal symptoms but some abuse potential  Needs to be prescribed in a subspecialty clinic 71

72.  buprenorphine (Suboxone)  Works by occupying opiate receptors without fully stimulating them  Will reduce withdrawal symptoms and may have less abuse potential than methadone  Prescribers must go through special training in order to prescribe 72

73.  imipramine (Tofranil)  Used to treat depression in consumer with opiate abuse/dependence  Treatment for depression with imipramine was associated with reduced craving for, and self- reported use of, opiates, cocaine, and cannabis 73

74.  Nicotine replacement  Works same way smoking and dipping does  May reduce craving by occupying and stimulating receptors  Available in multiple delivery systems 74

75.  buproprion (Zyban, Wellbutrin)  Works through the dopamine and norepinephrine system (presumably)  May reduce craving indirectly  Effect independent of antidepressant effect 75

76.  Varenicline (Chantix)  Works by occupying nicotinic receptors, blocking nicotine effects  May reduce craving by mildly stimulating receptors  Nicotinic receptors are odd: initially stimulated, then shut down  Insomnia, agitation, psychosis possible 76

77.  No medication approved for caffeine use/abuse  Caffeine blocks adenosine  Adenosine receptors in brain affect wakefulness  Adenosine receptors in the heart regulate rhythm  Adenosine receptors in stomach affect acid secretion 77

78.  Consumers on clozapine seem to have lower rates of substance abuse  Lithium for adolescents seems to reduce alcohol abuse 78

79.  Withdrawal from alcohol and benzos can be fatal  Withdrawal from opiates is very uncomfortable, with significant physical symptoms, but rarely fatal  Withdrawal from cocaine rarely requires close supervision 79

80.  Accessible  Capable  Comprehensive  Continuous  Integrated  Flexible  Individualized  Willing and Tolerant  Culturally competent

81.  Safe housing  Meaningful daytime activity  Sober support network  Positive alliance with at least one treatment provider  Social work interventions reduce stress, preserving brain function, and leading to better outcomes

82.  Can’t remember  Difficult medication schedule  Fear of medications  Bad side effects  No social support  Don’t have an illness, so don’t need medications  Stigma of taking a psychiatric medication  Don’t like/trust the prescriber  The meds aren’t working

83. Conditions that may be related to problems with brain regions that mediate facial recognition Capgras-delusion that family and friends are imposters Fregoli-delusion that one person is wearing many disguises, so multiple people are actually just one person Cotard-delusion that all of organs are gone or they are dead Autism and Aspergers-interpersonal difficulties may be related to inability to recognize facial expressions Depersonalization-delusion that the face in the mirror is not you

87.  Denial-you understand, on some level, your actions and consequences, but this understanding does not influence behavior  Anosognosia or lack of insight is the physical inability to understand your actions while sick  Anosognosia is more similar to amnesia than to denial

88.  Coercion assumes that the role of the treatment team is to be right and to minimize risk liabilities  Therefore, take the steps necessary to optimize a narrowly defined outcome (e.g. suicide prevention)  Hospitalization and symptom improvement most likely interventions when suicide risk acutely increased  Both are independent risk factors for completed suicide, so…what are we doing?  Recovery is a civil rights movement similar to the advances made by the physically disabled to (re-)integrate into the community  Society created accommodations for physically disabled (ramps, automatic doors, etc) so they could participate in society  Accommodations for the mentally ill were not included in this movement, necessitating a separate movement

89.  Basic tenets of the recovery movement include hope, engagement, supporting self-efficacy, and the dignity of risk  Treatment providers should take a consultative, rather than directive, role in the treatment of psychiatric illnesses; fewer appointments, and more walk- in availability  Note that recovery is not a synonym for symptom remission; consumers can be symptomatic and still participate in society  The role of any health care intervention is to shift the odds in your favor; ownership of outcomes cannot rest solely on health care providers  Psychiatric illness associated with increased mortality (life expectancy in your 50s), even when suicide excluded; so…what are we doing?

90.  Some have argued that coercive treatment is an accommodation for asognosia (lack of insight into need for treatment)  Others have argued that coercive treatment is a legitimate engagement tool, but should not be relied upon for prolonged periods of time  Still others argue that ATOs and recovery can never be reconciled, and they are even against involuntary hospitalization  Intensive outreach and engagement are the keys to recovery; court orders merely obligate staff to do the job they should be doing anyway (and without resorting to restrictions of liberty)  Do ATO’s reduce or increase autonomy?  Treatment Advocacy Center: “Severe mental illness, not its treatment, restricts civil liberties. By assuring timely and effective intervention for the disabling medical condition of severe mental illness, assisted outpatient treatment restores the capacity to exercise civil liberties and reduces the likelihood of the loss of liberty or life as a result of arrest, incarceration, hospitalization, victimization, suicide and other common outcomes of non-treatment.” Thanks for your time

91.  Thanks for your time!  Shout out to Dr Tom Coles, for finishing the Detroit Free Press/Talmer Bank Marathon and raising awareness for the Brain & Behavior Research Foundation (formerly NARSAD)