Neuro test 3

Treatment considerations with OCD Establish Rapport: incorporate patient's preferences into treatment plan --> Pharmacologic vs. non-pharmacologic therapy (3) (What is the recommended therapy for OCD) --> Benzodiazepines generally do NOT have a role in the treatment of OCD

-SSRIs and Clomipramine - CBT Recommended therapy for OCD

Course of Illness (schizophrenia) Abrupt OR insidious Prodromal phase Initial presentation usually with positive symptoms Couse is variably but most often this is a chronic illness Periods of exacerbation and recovery Periods of recovery can last for years Adherence to medication and psychosocial intervention can improve functioning and outcomes Early non-adherence increases hospitalizations

.

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013) Cont: Criterion F (required): Symptoms last for more than ___ month. Criterion G (required): Symptoms create distress or functional impairment (e.g., social, occupational). Criterion H (required): Symptoms are not due to ____, substance use, or other illness. ****Key is impact on ___/___/___****

1 medication Work/Love/Play

Prazosin As Adjunct for PTSD Dosing: Initiate: ____mg at bedtime Titrate by 1 mg every 2-3 days, then 2-5 mg per week Based on ADRs and patient response Maximum dose: ___ mg at bedtime Note: doses of up to 20 mg have been studied Monitoring: Adverse Effects: (5) Drug Interactions: Additive hypotensive effects when combined with other antihypertensive medications

1 16 dizziness, drowsiness, headache, orthostatic hypotension, syncope

Summary of OCD Treatment Guidelines •Both CBT and SSRIs/clomipramine are effective treatment modalities •SSRI preferred for first trial over clomipramine •Antidepressant doses are generally at the HIGHER end of the dosing range •Consider switching or augmenting agents if first trial ineffective •Adequate duration: at least __-__years

1-2

Epidemiology (UpToDate, 2022) Schizophrenia occurs throughout the world. The prevalence of schizophrenia approaches 1 percent internationally. The incidence is about 1.5 per 10,000 people. Age of onset is typically during late adolescence; childhood and late-life onset (over 45 years) are rare. Slightly more men are diagnosed with schizophrenia than women (on the order of 1.4:1) Women tend to be diagnosed later in life than men. Modal age of onset is between ___ to ___ for men and between ___ to ___ for women, with a second peak occurring around menopause There is also some indication that the prognosis is worse in men

18 and 25 25 and 35

OCD Epidemiology Affects ~ 5 million Americans (1 in 40 adults) Widely underdiagnosed Females > males In childhood, males > females Typical onset in childhood or adolescence Average age of onset:____ years Onset prior to 14 years occurs in about 25% cases Common comorbidities Other ____ disorder (75%) Mood disorder (63%)

19.5 anxiety

Mesolimbic dopamine hypothesis is the ___ hypothesis

2nd hypo and hyperactivity from dopamine

Acute Stress Disorder The development of specific fear behaviors that last from __days to__ month after a traumatic event. These symptoms occur after the patient has experienced or witnessed death or threat of death, serious injury or sexual assault. Physical attack, physical abuse, mugging, active combat, sexual violence, natural disaster and serious accidents. Acute stress disorder can also result from hearing about the violent or accidental trauma of a loved one, or repeated exposure to traumatic events (American Psychiatric Association, 2013).

3 1

What drugs can induce anxiety (9)

Antidepressants ( at first can make you feel anxious) Albuterol Levodopa stimulants pseudoephedrine levothyroxine (if dose is too high) Anticholinergics alcohol/sedative withdrawal Prednisone

What are the third generation Antipsychotics (3)

Aripiprazole Brexpiprazole Cariprazine

Generally Avoid for PTSD •_____ •Less effective •Receptor binding thought to be lower in the prefrontal cortex of patients with PTSD •Abuse potential •____ treatment outcomes Exposure based trauma therapy is the best thing for PTSD and _____ interfere with that by blunting your CNS AND ( the other drug class to avoid) •___ ____ •___in overdose •Less studied than SSRIs and SNRIs

Benzodiazepines Worsens Benzodiazepines AND Tricyclic Antidepressants Fatal

Treatment of Adults with OCD Assess patient's preference for pharmacologic therapy vs. non-pharmacologic therapy First-line treatment options: (3)

CBT SSRI or clomipramine Combination CBT + SSRI or clomipramine

Substance induced psychosis leading to future schizophrenia (2) what are the substances. etiology of schizophrenia: Perinatal insults Head injury famine parental age infection and autoimmune causes excessive pruning of synapses may be a factor in genetically predisposed individuals

Cannabis, Amphetamine (stimulants)

Clozapine was the first drug with a stronger ability to reduce negative symptoms and that causes fewer extrapyramidal symptoms than known to date antipsychotics. ___, however, is the one atypical antipsychotic recognized as particularly effective when other antipsychotic agents have failed, and is thus the "gold standard" for efficacy in schizophrenia. It may have a particular niche in treating aggression and violence in psychotic patients. The discovery of clozapine contributed to the introduction of new drugs with more beneficial pharmacological profile than first generation antipsychotics.

Clozapine

what are the 2nd generation antipsychotics (5)

Clozepine Olanzapine Quetiapine Risperidone Ziprasidone

____ Symptoms of schizophrenia _____dysfunction recently emphasized More common than generally realized (70%) Impairment of: ◦ Attention (maintain and shifting) ◦ Info processing speed ◦ Working memory and long-term memory ◦ Executive function ◦ Skill acquisition ◦ Associated w/ poor social & community function

Cognitive Cognitive

APA's Clinical Practice Guidelines for PTSD Strongly Recommended - Evidence Based Practice: ◦(4) Conditionally Recommended: ◦ Brief Eclectic Psychotherapy ◦ Eye Movement Desensitization and Reprocessing (EMDR) Therapy ◦Narrative Exposure Therapy (NET)

Cognitive Behavioral Therapy (CBT) ◦ Cognitive Processing Therapy (CPT) ◦ Cognitive Therapy ◦ Prolonged Exposure

Treatment of Schizophrenia First-Generation Antipsychotics (Typical) The first-generation antipsychotic drugs act mainly by blocking dopamine ___ receptors in the brain. They do not exhibit a selectivity for any of the dopamine pathways in the central nervous system and therefore can lead to a range of side-effects. Potency low to high Chlorpromazine Mesoridazine Molidone Perphenazine Trifluoperazine Thiothixene Fluphenazine Haloperidol

D2

Dopamine (DA) Hypothesis Potency of antipsychotic medication correlates with the amount of ____ receptor blockade. Drugs such as amphetamines, which increase ____activity, can cause a psychosis that mimics schizophrenia and can exacerbate schizophrenic symptoms. Positive or negative symptoms?

D2 DA

PTSD Specifiers - adult or child Dissociative* Specification - In addition to meeting criteria for diagnosis, an individual experiences high levels of either of the following in reaction to trauma-related stimuli: 1.____. Experience of being an outside observer of or detached from oneself (e.g., feeling as if "this is not happening to me" or one were in a dream). 2._____. Experience of unreality, distance, or distortion (e.g., "things are not real"). Delayed Specification - Full diagnostic criteria are not met until at least____months after the trauma(s), although onset of symptoms may occur immediately.

Depersonalization Derealization six

Treatment Considerations for PTSD (5)

MDD (major depressive disorder) Substance abuse/misuse Coexisting Anxiety Disorder Suicidal ideation Sleep Disturbances

Glutamate Theory of Schizophrenia Phencyclidine (PCP) induces psychosis PCP and ketamine (NMDA antagonist) block NMDA receptors ion channels led to hypothesis that schizophrenia may be a disorder of ____ hypofunction or inhibition

NMDAR (NMDA receptors)

____ Symptoms of schizophrenia Things that are ____: • Affect: Flattened or absent • Alogia "poverty of speech" • Anhedonia "lack of fun/joy" • Avolition "lack of motivation" • Psychomotor retardation • Lack of socialization • Loss of emotional "connectedness"

Negative subtracted

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013) Cont: Criterion D (two required): ___ thoughts or feelings that began or worsened after the trauma, in the following way(s): • Inability to recall key features of the trauma • Overly negative thoughts and assumptions about oneself or the world • Exaggerated blame of self or others for causing the trauma • Negative affect • Decreased interest in activities • Feeling isolated • Difficulty experiencing positive affect ****Key is ____ impact****

Negative psychological

What is the OCD Cycle (4)

Obsessions --> anxiety --> Compulsion --> relief Medications help mediate the obsession and the anxiety the obsessions create

Pharmacotherapy PTSD First line options (1) and what is the most common one? •Thought to help with intrusive thoughts, sleep disorders and nightmares •Do NOT usually help with avoidance symptoms •Consider: •Starting at lower doses and titrating slowly to avoid anxiety •Adequate trial is minimum of 6-8 weeks

SSRIs (you can use any SSRI for PTSD) sertraline

APA's Clinical Practice Guidelines for PTSD Medication is included in APA's Guidelines. Question: What class of medications would be used to treat PTSD?

SSRIs...we don't know why they work

____ Disorder DSM-5 requires at least 1 of the following symptoms for a significant portion of the time during a 1-month period: delusions, hallucinations or disorganized speech. Grossly disorganized behavior (catatonia) or the negative symptoms described above may also be present. Symptoms may have been present for less than a month, if they resolved after being treated. Symptoms must last more than a month but less than 6 months. There can be no manic, depressive or mixed manic-depressive episodes during these symptoms, and any mood disturbance must have been present during only a minority of this time, thereby excluding schizoaffective disorder or bipolar disorder with psychotic features.

Schizophreniform (pre schizophrenia)

Question: What medications/drugs could cause the physiological symptoms of schizophrenia? What medical/psychological conditions could mimic the physiological symptoms of schizophrenia?

Stimulants (crack cocaine) a ton, any CNS disturbance (post seizure, infection, diabetes, ) Concussions can cause schizophrenia later in life. ?

OCD is an _____/_____disorder

anxiety Thought

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013) Cont: Criterion E (two required): Trauma-related ___ and ___ that began or worsened after the trauma, in the following way(s): •Irritability or aggression • Risky or destructive behavior • Hypervigilance • Heightened startle reaction • Difficulty concentrating • Difficulty sleeping ****Key here is_____/____involvement****

arousal and reactivity sympathetic/HPA

long term goals of schizophrenia maintain ___ functioning

baseline

What Is Schizophrenia? Schizophrenia is a chronic ___ disorder - no cure for schizophrenia. It affects less than one percent of the U.S. population. Symptoms can include delusions, hallucinations, disorganized speech, trouble with cognition, and lack of motivation. Not schizophrenic, a person with ____. Elyn Saks: A tale of mental illness -- from the inside | TED Talk

brain schizophrenia

PTSD Child Specifier (younger than 6) Cont. The presence of one or more of the following: • spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic events (Note: Spontaneous and intrusive memories may not necessarily appear distressing and may be expressed as play reenactment.) • recurrent distressing ___ related to the content and/or feeling of the traumatic events (Note: It may not be possible to ascertain that the frightening content is related to the traumatic event.) •___as if the traumatic events are recurring; the most extreme being a complete loss of awareness of present surroundings. (Note: Such trauma-specific reenactment may occur in play.) • intense or prolonged psychological ____ at exposure to internal or external ___ • marked physiological reactions to reminders of the traumatic events

dreams reactions distress cues

Davis also hypothesized that negative symptoms of schizophrenia resulted from the ___ ____ hypodopaminergic and Positive symptoms were hypothesized to result from ____ hyperdopaminergic

frontal cortex accumbens

Cortical ___ ___ loss is higher in schizophrenia patients

gray matter

Cellular Pathology of schizophrenia Using human postmortem brain specimens, researchers found that the reduced volume of various brain regions was not due to a diminished number of cells, but rather to neurons having smaller somas, reduced dendritic trees and dendritic spine density, and increased cell packing. Several studies show that _____ cells of patients with schizophrenia are more_____ than those of healthy people and that selected cortical layers in the brains of patients with schizophrenia are atrophied.

hippocampal disorganized

In untreated schizophrenia, the mesolimbic dopamine pathway is hypothesized to be hyperactive, (indicated here by the pathway appearing red) as well as by the excess dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations. Administration of a D2 antagonist, such as a conventional antipsychotic, blocks dopamine from binding to the D2 receptor, which reduces ___ in this pathway and thereby reduces positive symptoms as well. Antipsychotics also block D2 receptors in the mesocortical DA pathway, where DA may already be deficient in schizophrenia (see Figures 4-14 through 4-16). This can cause or worsen negative and cognitive symptoms even though there is only a low density of D2 receptors in the cortex

hyperactivity

Definitions Psychosis -

loss of touch with reality. When someone experiences a psychotic episode, their thoughts and perceptions are disturbed, they may have difficulty understanding what is real and what is not.

SSRI or Clomipramine Monotherapy First-line option for patients with mild-moderate OCD who: Are not interested in CBT Prefer ____ over CBT Have previously responded positively to an SSRI or clomipramine

medication

Olanzapine/Samidorphan (ALKS 3831) Olanzapine/samidorphan is a combination therapy that includes a fixed dose of samidorphan (a μ-opioid receptor antagonist) and olanzapine The intended purpose of this combination therapy is to help reduce the olanzapine-associated weight gain and adverse ____ effects with samidorphan while maintaining the established therapeutic effect of olanzapine in the treatment of schizophrenia.

metabolic

For most conventional antipsychotics, the degree of D2 receptor binding in the mesolimbic pathway needed for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than 80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and in the pituitary is associated with hyperprolactinemia. Thus, there is a ____ window between the _____ for antipsychotic efficacy and that for side effects in terms of D2 binding.

narrow threshold

UCR and NIBRS The Uniform Crime Reporting program compiles official data on crime in the United States, published by the FBI. Data is reported by participating law enforcement agencies through the National Incident-Based Reporting System (NIBRS). Data is reported annually, but it lags behind by a few years. 2019 is the current data reporting year. Question: What kind of crime is going to be reported by law enforcement agencies? Hint - what is going to be required for police involvement?

only the ones that police get called into

DA in arcuate n. of hypo inhibits prolactin release from ant pit. Inhibiting D2 receptors increases ___ - hyperprolactinemia Prolactin elevation Dopamine D2 receptors in the tuberoinfundibular DA pathway are also blocked by conventional antipsychotics, and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia. This is associated with conditions called____ (i.e., breast secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid demineralization of bones, especially in postmenopausal women who are not taking estrogen replacement therapy. Other possible problems associated with elevated prolactin levels may include sexual dysfunction and weight gain, although the role of prolactin in causing such problems is not clear. This is associated with conditions called galactorrhea (i.e., breast secretions) and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia may thus interfere with fertility, especially in women. Hyperprolactinemia might lead to more rapid demineralization of bones, especially in postmenopausal women who are not taking estrogen replacement therapy. Other possible problems associated with elevated prolactin levels may include ____ dysfunction and weight gain, although the role of prolactin in causing such problems is not clear.

prolactin galactorrhea sexual

schizophrenia Some type of insult occurs at a neurodevelopment stage resulting in altered neurodevelopment Some insults hypothesized include viruses, infections, release/increase in proinflammatory cytokines Produces alteration in neuronal density and size, glial proliferation and increased synaptic___

pruning ( schizophrenia patients have less dendritic spines)

OCD Tx SRIs include clomipramine and all of the___ ___ ___ __ (SSRIs). Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline are approved by the FDA for treatment of OCD. Strong empirical evidence supports using ___ that relies primarily on the behavioral technique of exposure and response prevention (ERP). Relaxation therapy - SNS/PNS, reciprocal inhibition.

selective serotonin reuptake inhibitors CBT

Clomipramine: Overview MOA: Dibenzazepine tricyclic antidepressant Principal mechanism (in OCD) Inhibition of the reuptake of ____ (5-HT) into the pre-synaptic terminal FDA-Approved Indications: OCD Pharmacokinetics: Substrate of ____ Drug-drug interactions with fluvoxamine, fluoxetine, sertraline, paroxetine Highly ___ bound ___ prolongation Undergoes hepatic metabolism

serotonin CYP2D6 protein QT (because sodium channel blocking)

Hippocampus an schizophrenia There is evidence of hippocampal abnormality in schizophrenia. -Hippocampi ___ in brains of schizophrenics at autopsy and in vivo than controls (multiple studies). -Smaller hippocampi in 13/15 affected co-twins in a study of monozygotic twins discordant for schizophrenia. -Hippocampal neuronal size and density appear to be decreased. -Supporting evidence of decreased or abnormal synaptic function.

smaller

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013): Criterion A (one required): The person was exposed to: death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence, in the following way(s): • Direct exposure • Witnessing the trauma • Learning that a relative or close friend was exposed to a trauma •Indirect exposure to aversive details of the trauma, usually in the course of professional duties (e.g., first responders, medics) ****Here the important note is ___ __ to trauma****

direct exposure

Hypothesis of having hypodominergic activity.... from cell samples from deceased people Cellular/morphological evidence of dopamine hypofunction in prefrontal cortex in schizophrenia. In schizophrenia patients there was less___ ____(which is the rate limiting enzyme to make catecholamines)

tyrosine hydroxylase

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013) Cont: Criterion C (one required): Avoidance of trauma-related stimuli after the trauma, in the following way(s): (2)

• Trauma-related thoughts or feelings • Trauma-related reminders

Simplified PTSD DSM-5 Diagnostic Criteria (APA, 2013) Cont: Criterion B (one required): The traumatic event is persistently reexperienced, in the following way(s): (5)

• Unwanted upsetting memories • Nightmares • Flashbacks • Emotional distress after exposure to traumatic reminders • Physical reactivity after exposure to traumatic reminders

Goals of Treatment of OCD (3)

•Decrease symptom frequency and severity •Improve functioning •Improve quality of life

Clinical Signs & Symptoms of PTSD (4)

•Negative alterations in cognition and mood •Reexperiencing •Avoidance •Arousal (hypervigilance)

APA's Clinical Practice Guidelines for PTSD Strongly Recommended - Evidence Based Practice: ◦ Cognitive Behavioral Therapy (CBT) ◦ Cognitive Processing Therapy (CPT) ◦ Cognitive Therapy ◦ Prolonged Exposure Conditionally Recommended:(3)

◦ Brief Eclectic Psychotherapy ◦ Eye Movement Desensitization and Reprocessing (EMDR) Therapy ◦Narrative Exposure Therapy (NET)

Combination CBT and Pharmacologic Tx what is the 1st line treatment for severe OCD???? (2)

SSRI or clomipramine ++++ CBT

Treatment of Schizophrenia Second-Generation Antipsychotics (Atypical) Generally, second generation drugs, in comparison with classical antipsychotics, exhibit higher ability to block serotonin _____ receptors than dopamine ___ receptors. Block serotonin 5-HT2A receptors in cortex and striatum increases dopamine Additionally, antagonism to D2 receptors is weaker in the case of second-generation antipsychotics comparing to those of first generation, which manifests in lower occurrence of ____ side effects. There are also hypotheses that suggest that atypical antipsychotics bind to dopamine receptors with high ____ rates or that they are more likely to block dopamine receptors in cortical and limbic regions than in nigrostriatal pathway, which also contributes to lower risk of extrapyramidal effects

5-HT2A D2 extrapyramidal dissociation

____partial agonism can also make an antipsychotic atypical Olanzapine lacks the extreme ___ properties of clozapine, but can be somewhat sedating in some patients, as it does have antagonist properties at M1-muscarinic, H1-histaminic, and α1-adrenergic receptors Olanzapine is consistently associated with weight gain, perhaps because of its antihistaminic and 5HT2C antagonist properties (Figures 5-36 and 5-46). It ranks among the antipsychotics with the greatest known ____ risks, as it robustly increases fasting triglyceride levels and increases insulin resistance The major differentiating feature of ziprasidone is that it has little or no propensity for ____ ___, despite its moderate 5HT2C and H1 antagonist actions (Figure 5-56). Furthermore, there seems to be little association of ziprasidone with dyslipidemia, elevation of fasting triglycerides, or insulin resistance

5HT1A sedating cardiometabolic weight gain

Thus, ___ antagonism in the cortex hypothetically stimulates downstream dopamine release in the____. It does this by reducing glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory GABA at dopamine neurons there. Release of dopamine from neurons downstream in the striatum is thus disinhibited, which should theoretically mitigate ____. dopamine can then compete with the SDA for the D2 receptor and reverse the inhibition there. As D2 blockade is thereby reversed, SDAs cause little or no extrapyramidal symptoms (EPS) or___ ____ If 5HT2A receptors on glutamatergic pyramidal neurons are blocked, then these neurons cannot be activated by serotonin release in the cortex (indicated by the dotted outline of the glutamatergic neuron). (2) If glutamate is not released from glutamatergic pyramidal neurons into the brainstem, then GABA release is not stimulated and in turn cannot inhibit dopamine release from the substantia nigra into the striatum. Can increase dopamine in prefrontal cortex, and in striatum - reduces EPS

5HT2A striatum EPS (extra pyramidal symptoms) tardive dyskinesia.

___ ___ ___ Disorder DSM-5 Diagnostic Criteria: A. A pattern of behavior in which a child ___ approaches and interacts with unfamiliar adults and exhibits at least two of the following: • Reduced or absent reticence in approaching and interacting with unfamiliar adults. • Overly familiar verbal or physical behavior (that is not consistent with culturally sanctioned and with age-appropriate social boundaries). • Diminished or absent checking back with adult caregiver after venturing away, even in unfamiliar settings. • Willingness to go off with an unfamiliar adult with little or no hesitation. B. The behaviors in Criterion A are not limited to impulsivity (as in Attention Deficit/Hyperactivity Disorder) but include socially ____ behavior. C. The child has exhibited a pattern of extremes of ____ care as evidenced by at least one of the following: • Social neglect or deprivation in the form of persistent lack of having basic emotional needs for comfort, stimulation and affection met by caregiving adults. • Repeated changes of primary caregivers that limit ability to form stable attachments (e.g., frequent changes in foster care). • Rearing in unusual settings that severely limit opportunities to form selective attachments (e.g., institutions with high child to caregiver ratios). D. The care in Criterion C is presumed to be responsible for the disturbed behavior in Criterion A (e.g., the disturbances in Criterion A began following the pathogenic care in Criterion C). E. The child has a developmental age of at least nine months. Specify if Persistent: The disorder has been present for more than 12 months. Specify current severity: Disinhibited Social Engagement Disorder is specified as severe when a child exhibits all symptoms of the disorder, with each symptom manifesting at relatively high levels.

Disinhibited Social Engagement actively disinhibited insufficient

____ Prefrontal Cortex Damage (loss of neurons) to DLPFC causes characteristic deficits. -Lack of initiation due to decreased environmental scanning -Poor cognitive flexibility due to difficulty shifting attention - stimulus boundedness -Lack of emotional spontaneity (abulia) probably due to poor perception of hedonic events. -Decrement in interpersonal involvement secondary to the above deficits. -Poor self care due to lack of initiation, decreased ability to learn from complex social feedback. These deficits are essentially identical to the ___symptoms of schizophrenia.

Dorsolateral negative

CBT Monotherapy (OCD) ___-line treatment option in patients that meet the following criteria: ___-____ severity Prefer non-pharmacologic therapy Adequate trial 13-20 weeks of weekly sessions; OR, Three weeks of daily sessions

First Mild to moderate

Studies show that both___ synthesis and uptake are reduced in a subset of GABA prefrontal cortex neurons In schizophrenics - and may contribute to prefrontal cortical ____ in this disorder.

GABA dysfunction

schizophrenia is associated with hypofunction of N-methyl-Daspartate glutamate receptors (NMDAR), leading to decreased activity of ____ inhibitory interneurons and disinhibited glutamate release in target regions. Non-competitive NMDAR antagonists, such as ketamine, are hypothesized to preferentially block NMDA receptors expressed on GABAergic chandelier cells, leading to reduced GABA input to glutamatergic pyramidal neurons, resulting in excess glutamate (Glu) release in terminal areas. A similar mechanism has been hypothesized to underlie schizophrenia, with functionally impaired chandelier cells leading to aberrant firing of pyramidal neurons, and persistent cortical glutamate release. NMDAR antagonist administration mimics not only the positive, but also the negative and cognitive symptoms of schizophrenia

GABA --> increases glutamate transmission in the prefrontal cortex.

Etiology: _____ 10-fold risk among first-degree relatives 35% risk for children with both parents with schizophrenia ~50% concordance among monozygotic twins ~25% concordance among dizygotic twins Specific genetic locations have been identified that are associated with schizophrenia.

Genetic

SCZ show decreased expression of genes associated with: Presynaptic secretory machinery (2) there are a number of genes in people with schizophrenia that are less and some that are more in comparison to people with out schizophrenia

Glutamate GABA

___ ____ ____ ____ (OCPD) is marked by an excessive need for orderliness, neatness, and perfectionism. The most common personality disorder "a pervasive pattern of preoccupation with orderliness, perfectionism, and mental and interpersonal control, at the expense of flexibility, openness, and efficiency, beginning by early adulthood and present in a variety of contexts" Is preoccupied with details, rules, lists, order, organization, or schedules to the extent that the major point of the activity is lost. Shows perfectionism that interferes with task completion (e.g., is unable to complete a project because his or her own overly strict standards are not met). Is excessively devoted to work and productivity to the exclusion of leisure activities and friendships (not accounted for by obvious economic necessity). Is overconscientious, scrupulous, and inflexible about matters of morality, ethics, or values (not accounted for by cultural or religious identification). Is unable to discard worn-out or worthless objects even when they have no sentimental value. Is reluctant to delegate tasks or to work with others unless they submit to exactly his or her way of doing things. Adopts a miserly spending style toward both self and others; money is viewed as something to be hoarded for future catastrophes. Shows rigidity and stubbornness.

Obsessive Compulsive Personality Disorder

Different types of Schizophrenia Paranoid Type ? Disorganized Type ? Catatonic Type ? Undifferentiated type and residual type

Paranoid Type --> they are coming to get me Disorganized Type --> emotional affect does not match information given to them (laughing that their cat got ran over) Catatonic Type - 1. excessive motor activity that is apparently purposeless and not influenced by external stimuli.. negativism ... and mutism... 2. Waxy type can be posed Undifferentiated type and residual type:

_____ Symptoms of schizophrenia Things that are ____ - exaggerations or distortions of normal thoughts, emotions, and behaviors: • Hallucinations • Delusions • Disorganized speech • Loose associations • Tangentiality • Incoherent speech • Disorganized thoughts • Grossly disorganized • Catatonic behavior*

Positive added

___ As Adjunct for PTSD 50-70% of patients with PTSD report nightmares Likely due to increased CNS adrenergic activity Prazosin (Minipress®) Alpha-1 adrenergic antagonist Lipid soluble Other alpha-1 antagonists are not and should not be recommended Mechanism of action for PTSD nightmares: Blunts ____ activity at alpha-1 receptors in CNS Reduces severity of nightmares and physical reactivity; may increases REM sleep and overall sleep time

Prazosin norepinephrine

___ ___ ___ DSM-5 Diagnostic Criteria: A. A consistent pattern of inhibited, emotionally withdrawn behavior toward adult caregivers, manifested by both of the following: The child rarely or minimally seeks comfort when distressed. The child rarely or minimally responds to____when distressed B. A persistent social or emotional disturbance characterized by at least two of the following: • Minimal social and emotional responsiveness to others • Limited positive affect • Episodes of unexplained irritability, sadness, or fearfulness that are evident even during ____ interactions with adult caregivers. C. The child has experienced a pattern of extremes of____ care as evidenced by at least one of the following: • Social neglect or deprivation in the form of persistent lack of having basic emotional needs for comfort, stimulation, and affection met by caring adults • Repeated changes of primary caregivers that limit opportunities to form stable attachments (e.g., frequent changes in foster care) • Rearing in unusual settings that severely limit opportunities to form selective attachments (e.g., institutions with high child to caregiver ratios) D. The care in Criterion C is presumed to be responsible for the disturbed behavior in Criterion A (e.g., the disturbances in Criterion A began following the lack of adequate care in Criterion C). E. The criteria are not met for autism spectrum disorder. F. The disturbance is evident before age ___ years. G. The child has a developmental age of at least ___ months. Specify if Persistent: The disorder has been present for more than 12 months. Specify current severity: Reactive Attachment Disorder is specified as severe when a child exhibits all ___ of the disorder, with each symptom manifesting at relatively high levels.

Reactive Attachment Disorder comfort nonthreatening insufficient 5 nine symptoms

Trauma- and Stressor- Related Disorders DSM-5 This is a new category added to DSM-5. Moved from Anxiety Disorders. There are distinct categories within that reflect very different presentations: (5) of them

Reactive Attachment Disorder (Child Disorders Only) Disinhibited Social Engagement Disorder (Child Disorders Only) Posttraumatic Stress Disorder (PTSD) Acute Stress Adjustment Disorder

Obsessive-Compulsive Disorder DSM-5 Diagnostic Criteria (300.3): A. Presence of obsessions, compulsions, or both: Obsessions are defined by (1) and (2): 1. ____ and ___ thoughts, urges, or impulses that are experienced, at some time during the disturbance, as intrusive and ___, and that in most individuals cause marked anxiety or distress. ****This is the ___ part*** 2. The individual attempts to ignore or suppress such thoughts, urges, or images, or to ___ them with some other thought or action (i.e., by performing a compulsion). ****___ part**** B. The obsessions or compulsions are time-consuming (e.g., take more than 1 hour per day) or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The obsessive-compulsive symptoms are not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition. D. The disturbance is not better explained by the symptoms of another mental disorder (e.g., excessive worries, as in generalized anxiety disorder; preoccupation with appearance, as in body dysmorphic disorder; difficulty discarding or parting with possessions, as in hoarding disorder; hair pulling, as in trichotillomania [hair-pulling disorder]; skin picking, as in excoriation [skinpicking] disorder; stereotypies, as in stereotypic movement disorder; ritualized eating behavior, as in eating disorders; preoccupation with substances or gambling, as in substance-related and addictive disorders; preoccupation with having an illness, as in illness anxiety disorder; sexual urges or fantasies, as in paraphilic disorders; impulses, as in disruptive, impulse-control, and conduct disorders; guilty ruminations, as in major depressive disorder; thought insertion or delusional preoccupations, as in schizophrenia spectrum and other psychotic disorders; or repetitive patterns of behavior, as in autism spectrum disorder). Specify if: With good or fair insight: The individual recognizes that obsessivecompulsive disorder beliefs are definitely or probably not true or that they may or may not be true. With poor insight: The individual thinks obsessive-compulsive disorder beliefs are probably true. With absent insight/delusional beliefs: The individual is completely convinced that obsessive-compulsive disorder beliefs are true. Specify if: Tic-related: The individual has a current or past history of a tic disorder.

Recurrent and persistent unwanted obsession neutralize Compulsion

Pharmacotherapy PTSD 2nd line option

SNRI (venlafaxine)

SSRIs & Clomipramine: Considerations in OCD SSRIs vs. clomipramine Similar efficacy ___ preferred over clomipramine for first trial Maintenance doses sometimes higher than ___ dose stated in package insert Titrate slowly! Adequate trial length 4-6 weeks at maximum tolerated dose May be even longer (10-12 weeks)

SSRI maximum

Dopamine Hypothesis of Schizophrenia? ..... first version of the dopamine hypothesis could be entitled the dopamine receptor hypothesis. It emerged from the seminal work of Carlsson and Lindqvit on the discovery of antipsychotic drugs, chlorpromazine and haloperidol not until the 1970s, however, that the dopamine hypothesis was finally crystallized with the finding that the clinical effectiveness of antipsychotic drugs was directly related to their affinity for dopamine receptors. The focus at the time was on excess transmission at dopamine receptors and blockade of these receptors to treat the psychosis Also, amphetamine increases synaptic monoamine levels, can induce psychotic symptoms - ____-induced psychosis provided additional evidence.

Too much dopamine in the nerve cells in psychosis amphetamine

Definitions PTSD is a ____ and _____-Related disorder that follows the occurrence of a traumatic event that is outside the ___ of normal human experience that: Poses ___ or ____ death or injury and produces intense fear, helplessness, or horror; and Would be considered distressing by almost anyone who underwent the event

Trauma and Stress range actual threatened

Therapeutic Considerations Frequent associations with TBI (___ ____ ___ )in practice lots of research ongoing in this area Overall, response rates for PTSD treatment remain fairly poor Rarely > 60% Less than ___% of patients achieve full ____ Given this, will see application of: SGAs TMS (transcranial magnetic ) Various psychotherapies More aggressive approach to management of other co-morbid illnesses (e.g., depression, SUD)

Traumatic brain injury 30 remission

DSM-5 Schizophrenia Diagnostic Criteria (APA, 2013) 1. Two or more of the following for at least 1 month (or longer period of time), and at least one of them must be a 1, 2, or 3: (5) Signs of the disturbance continue for 6 months or longer. This period must include at least __ full month of symptoms that meet the first criteria and may include periods of residual symptoms. During these residual periods, the signs of the disturbance may be manifested only by negative symptoms or by two or more symptoms outlined in the first criteria, only in a lesser form. The disturbance cannot be better explained by schizoaffective disorder, ___ or bipolar disorder because either: No major depressive or manic episodes have occurred concurrently with the active-phase symptoms or... If mood episodes have occurred during active phase symptoms, it's been for a minor amount of time. The disturbance cannot be attributed to the physiological effects of a substance (e.g., a drug of abuse or medication) or another medical condition If the individual has a history of autism spectrum disorder or a communication disorder of childhood onset, the additional diagnosis of schizophrenia is only made if ____ or ____ as well as the other required symptoms of schizophrenia are present for a month or more

delusions hallucinations disorganized speech grossly disorganized or catatonic behavior negative symptoms, such as diminished emotional expression 1 depressive delusions or hallucinations

Novel antipsychotic - Lumateperone (CAPLYTA) Lumateperone tosylate (ITI-007 tosylate, ITI-722) is a first-in-class investigational drug which acts synergistically through multiple systems (serotonergic, dopaminergic and glutamatergic), thus representing a unique approach for the therapeutic management of a range of neuropsychiatric disorders. It possesses a potent antagonistic activity at 5-hydroxytryptamine (serotonin) 2A (5-HT2A) receptors and also binds to dopamine (D1, D2) receptors with partial agonism at presynaptic D2 receptors and postsynaptic antagonism (D2). Preclinical data demonstrated that lumateperone uniquely acts as an indirect modulator of glutamatergic phosphoprotein with D1-dependent augmentation of both NMDA and AMPA activity via the mammalian target of rapamycin (mTOR) pathway, mechanisms thought to predict potent and rapid antidepressant effects. Previous results of schizophrenia efficacy studies found robust improvements in depressive as well as psychotic symptoms for those patients who were comorbidly ___. Received approval in December 2019 for the treatment of schizophrenia in adults. Also, treatment agitation associated with dementia and bipolar disorder.

depressed

PTSD Child Specifier (younger than 6) Exposure to actual or threatened death, serious injury, or sexual violation: • ___ experience • witnessing the events as they occurred to others, especially primary caregivers (Note: Does not include events witnessed only in electronic media, television, movies, or pictures.) •learning that the traumatic events occurred to a parent or caregiving figure

direct

Treatment of Schizophrenia First-Generation Antipsychotics (Typical) Side Effects block Alpha 1 HI M1 In addition to blocking D2 receptors in all dopamine pathways, One particularly important pharmacologic action of some conventional antipsychotics is their ability to block muscarinic M1-cholinergic receptors. This can cause undesirable side effects such as (4) These include generally undesired blockade of histamine H1 receptors (Figure 5-9) causing (2), as well as blockade of α1-adrenergic receptors causing cardiovascular side effects such as (2) and also _____-___ side effects which are caused by blocking dopamine in the striatum which have a inhibitory function on cholinergic cells --> which causes extra ACh activity in the striatum which causes the above ..... _____ drugs reduce the symptoms of Parkinson's disease and the side effects of antipsychotic drug treatment. ____ ____-- > This upregulation may be the consequence of the neuron's futile attempt to overcome drug-induced blockade of its dopamine receptors. ___ ___ ___ (rare) ______

dry mouth, blurred vision, constipation, and cognitive blunting weight gain and drowsiness orthostatic hypotension and drowsiness. extra-pyramidal Anticholinergic Tardive dyskinesia Neuroleptic Malignant Syndrome Hyperprolactinemia

Dopaminergic alterations have emerged in schizophrenia: 1. DA synthesis and release capacity are increased in the striatum. Baseline levels of DA are also ____, indicating higher resting levels of DA 2. Although needing replication, DA release capacity in prefrontal cortical and other extrastriatal regions is decreased. 3. Increased ___ receptors in the basal ganglia, nucleus accumbens, and substantia nigra of postmortem schizophrenic brains. PET scan also suggests increased D2 receptors in drug-free patients with schizophrenia

elevated D2

Dr. Wilkening says the way ocd is treated is ____

exposure to anxiety provoking events and how to cope with them.

Definitions Delusions -

fixed false beliefs held despite clear or reasonable evidence to the contrary. Types = persecutory (or paranoid), erotomanic, grandiose, jealous, somatic.

Neuroleptic Malignant Syndrome NMS is very rare. Only about 1 to 2 out of every 10,000 people who take antipsychotic drugs get it. Central dopamine receptor blockade in the hypothalamus may cause ____ and other signs of dysautonomia. An alternative theory is that ____ and muscle damage represent a primary effect on the peripheral muscle system, perhaps from direct changes in muscle mitochondrial function]. This in itself may represent a primary skeletal muscle defect or a direct toxic effect by these drugs on skeletal muscle. A primary role has also been proposed for a disrupted modulation of the sympathetic nervous system, manifesting in increased muscle tone and metabolism and unregulated sudomotor and vasomotor activity; these in turn lead to ineffective heat dissipation, and labile blood pressure and heart rate. In this model, dopamine antagonists precipitate symptoms by destabilizing normal dopamine _____ of efferent sympathetic activity.

hyperthermia rigidity regulation

"modified dopamine hypothesis of schizophrenia'' - Version II In 1991, Kenneth Davis published a landmark article - that reconceptualized the dopamine hypothesis in the light of the findings available at the time. The main advance was the addition of regional specificity into the hypothesis to account for the available human postmortem and metabolite findings, imaging data, and new insights from animal studies into cortical-subcortical interactions of DA . Davis proposed that schizophrenia is characterized by _____ activity in the ____ cortex (mesocortical system) And ______ activity in the ventral striatum/_____ accumbens (mesolimbic system). Davis also hypothesized that negative symptoms of schizophrenia resulted from the frontal cortex hypodopaminergic and Positive symptoms were hypothesized to result from accumbens hyperdopaminergic

hypodopaminergic frontal hyperdopaminergic nucleus

PTSD Child Specifier (younger than 6) Cont. Two or more of the following: • irritable, angry, or aggressive behavior, including extreme temper tantrums • hypervigilance • exaggerated startle response • problems with concentration • difficulty falling or staying asleep or restless sleep Also, clinically significant distress or ___ in relationships with parents, siblings, peers, or other caregivers or with school behavior not attributable to another medical condition.

impairment

Schizoaffective Disorder Mood symptoms and psychosis are prominent features of schizoaffective disorder (American Psychiatric Association, 2013). Concisely defining schizoaffective disorder has been a rather complex issue fraught with disagreement over whether or not it should be diagnosed as a distinct psychiatric disorder (Pagel et al., 2013). Characterized by a bout of illness during which a significant mood episode is manifested. Hallucinations and delusions must also be present in a time span of 2 weeks in order for a diagnosis of schizoaffective disorder to be accurately made.

is when you get mood disorders on top of having schizophrenia

Treatment of Schizophrenia Third-Generation Antipsychotics The newest group of antipsychotic drugs, described as the third generation, consists of aripiprazole, brexpiprazole and cariprazine. That group has been individualized on the grounds of their mechanism of action on dopamine receptors. Unlike other neuroleptics, third-generation drugs are not dopamine D2 receptor antagonists but D2 __ ___. The D2 receptor partial agonist properties of aripiprazole concern inhibition of cAMP accumulation through the dopamine D2 receptor (i.e., Gα signaling). Contrarily, when extracellular dopamine concentration is on a low level (e.g., in dopamine circuits that are involved in working memory), aripiprazole can bind to additional receptors and activate them partially. Hence, aripiprazole is termed as "___ ____"

partial agonists dopamine stabilizer

Definitions Hallucinations -

perception in the absence of a stimulus. Hearing, seeing, smelling, tasting, or feeling something that is not there. Auditory hallucinations, "hearing voices," are most common in schizophrenia and related disorders.

Treatment approach of Schizophrenia (3)

pharmacotherapy (important to limit positive symptoms) Psychosocial rehabilitation social support

PTSD Child Specifier (younger than 6) Cont. One of the following related to traumatic events: • persistent avoidance of activities, places, or physical reminders • people, conversations, or interpersonal situations that arouse recollections • diminished interest or participation in significant activities such as play •socially withdrawn behavior • persistent reduction in expression of___emotions

positive

Long-term blockade of D2 receptors in the nigrostriatal dopamine pathway can cause upregulation of those receptors, which may lead to a hyperkinetic motor condition known as ___ ___, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movements. This upregulation may be the consequence of the neuron's futile attempt to overcome drug-induced blockade of its dopamine receptors. Is there any way to predict those who will be harmed with the development of tardive dyskinesia after chronic treatment with conventional antipsychotics? Patients who develop EPS early in treatment may be ____ as likely to develop tardive dyskinesia if treatment with a conventional antipsychotic is continued chronically. Also, specific genotypes of dopamine receptors may confer important genetic risk factors for developing tardive dyskinesia with chronic treatment using a conventional antipsychotic. Risk of new cases of tardive

tardive dyskinesia twice

Dopamine Hypothesis of Schizophrenia: Version III O. D. Howes & S. Kapur, 2009 Four components The hypothesis has 4 distinctive components. 1.multiple ''hits (___ ___ ____)'' interact to result in dopamine ____—the final common pathway to psychosis in schizophrenia. 2.the locus of dopamine dysregulation moves from being primarily at the postsynaptic D2 receptor level to being at the presynaptic dopaminergic nerve terminal control level 3.Dopamine dysregulation is linked to "psychosis'' rather than schizophrenia specifically, perhaps the term ''___ ____.'' 4.Dopamine dysregulation is hypothesized to alter the appraisal of _____, perhaps through a process of aberrant salience. suggests that dopaminergic dysfunction may contribute to a more multifaceted misattribution of salience (a striking point or feature : highlight.) involving both rewarding and aversive signaling.

unrelated environmental events dysregulation psychosis proneness stimuli

Etiology of Schizophrenia Thought to be multifactorial, with "multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors" (Neidhart, 2016). Accumulating evidence has revealed a wide range of brain abnormalities (Benson and Feinberg, 2011): Abnormalities found in postmortem studies and in CT and MRI studies: ◦ enlarged lateral and third ____ ◦ loss of total gray matter, frontal, and temporal lobe volume ◦ reduction in total brain ___

ventricles size

Valbenazine and deutetrabenazine for Tardive Dyskinesia Valbenazine and deutetrabenazine, both received FDA approval for the treatment of TD. ___ ____ _____ 2 (VMAT2) inhibitors (transporter that puts monoamines in synaptic vesicles) Effective in treating Huntington's disease (HD)-associated chorea and tardive dyskinesia (TD) are hyperkinetic movement disorders that can have deleterious effects on patients' quality of life. Deutetrabenazine demonstrates consistent efficacy across patient types regardless of underlying psychiatric illness, or through use of dopamine-receptor antagonists (primary cause of TD). Long-term extension studies in both HD-associated chorea and TD show consistent efficacy and safety. Deutetrabenazine will likely be an integral part of the treatment strategy for HD-associated chorea and TD. Meanwhile, its potential to treat other hyperkinetic movement disorders is still under investigation.

vesicular monoamine transporter

third generation Antipsychotics affinity for blocking 5HT2A that is equal to or greater than their affinity for blocking D2 receptors, the amount of D2 antagonism in the striatum is lowered at the same dose where the drugs have antipsychotic actions. This creates a ____ between the dose that exerts antipsychotic actions and the dose that causes EPS or elevated prolactin levels

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