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Psychotic & Sleep Disorders

Psychopharmacology 101

For Non-prescribing

Mental Health Professionals -

A Training Resource

By Jim Messina, Ph.D., CCMHC, NCC, DCMHS-T

Psychotic Disorders

Psychotic: One who has broken with reality and/or unable to integrate thought & feeling

Not oriented X 4 (orirented to: self, others, place, time)

Positive Symptoms added to normal consciousness

  • Delusions
  • Hallucinations

Negative Symptoms – 5 A’s subtracted from normal consciousness

  • Affect (flat)
  • Anhedonia no pleasure
  • inAttention
  • Alogia
  • Avolition


Dopamine Theory of Schizophrenia

Carlsson & Lindquist (1963): Block Dopamine; D2 Antagonist & Reduce Symptoms

Newest Theory “Cognitive Dysmetria”: Decreased function between cerebellar/thalamic/cortical circuity & Poor Mental Coordination


New Terminology

“Deficit Schizophrenia” : Term used to identify subgroups of patients who present with enduring positive and negative symptoms

  • Typical old ones
  • Atypical new ones
  • Third Generation


Neurochemistry of Psychosis(?) don’t know the cause

• Etiology of Schizophrenia: Unknown

• Emil Kraepelin’s Confusion & von Economo’s encephalitis lethargica

• Theory: Block Dopamine, Decrease Psychosis (Carlsson & Lindquist Theory of Schizophrenia, 1963)

• D2 Antagonist

– Thorazine

– Haldol

• Neurotransmitters Involved

• Dopamine Pathways

– Meso-cortical – Negative Symptoms

• 5A’s (Affect, Anhedonia, Attention, Alogia & Avolution

– Meso-limbic – Positive Symptoms

• Delusions & Hallucinations

– Tuberoinfundibular – Hormonal (Prolactin)

– Nigrostriatal -- MOVEMENT

– 2 Pathways with Unidentified Function

• Incerto-Hypothalamic

• Medullary Pariventricular


What makes newer atypicals different from older typicals?

(1) Newer

What makes newer atypicals different from older typicals?

(1) Newer

(2) Movement Disorders Unlikely What makes newer atypicals different from older typicals?

(1) Newer

(2) Movement Disorders Unlikely

(3) But, there’s a better reason Why makes newer atypicals different from older typicals? Their dissociation constant (Kd)

Kd = concentration at which 50% of binding sites are occupied by drug.



Typicals & Atypicals

First Generation Typicals: Dopamine 2 Antagonists; Also M1, α1, H1 antagonists - Mechanism of Action: D2 Antagonist

  • Thorazine®
  • Haldol ® 

WARNING: Movement Disorders & Slower Dissociation


Typicals - DA2 Antagonists

  • Thioridazine (Mellaril)
  • Chlorpromazine (Thorazine)
  • Mesoridazine (Serentil)
  • Perphenazine (Trilaphon)
  • Trifluoperazine (Stelazine)
  • Fluphenazine (Prolixin)
  • Thiothixene (Navane)
  • Haloperidol (Haldol)
  • Loxapine (Loxitane)
  • Molindone (Modane)


Newer Atypicals (SDAs) Serotonin-Dopamine Antagonists But Really - Serotonin-Dopamine-Glutamate Antagonists

Second Generation: Rapid Dissociation; Reduced Risk of Tardive Dyskinesia; More mood improvement with potential Metabolic Syndrome (possible diabetes)


  • Ziprasidone (Geodon®) give with food
  • Risperidone (Risperdal®) prodrug-it is inactive and liver turns into invega
  • Olanzapine (Zyprexa®) M3 receptor, don’t use with diabetic
  • Quetiapine (Seroquel®) - Norquetiapine = NRI only on with 3
  • Asenapine (SAPHRIS®) – will not dissolve in stomach
  • Clozapine (Clozaril®) – 1958 does not cause movement disorder
  • Lurasidone (Latuda®)
  • Iloperidone (Fanapt®)
  • Paliperidone (Invega®, Invega Sustenna®, Invega Trinza® -- first 3 month injectable

Drug Action & DA Pathways





D2 Antagonists



Antagonists (SDAs)



Blocks D2

Therapeutic Action

Increase Negative Symptoms


Unblocks D2



Blocks D2

Therapeutic Action

DecreasePositive Symptoms

Sustains Block D2

“Fails to Reverse Block”




Blocks D2

Unwanted Side Effects

Movement Disorders


Unblocks D2




Blocks D2

Unwanted Side Effects

Prolactin Increase


Unblocks D2



DA Pathways Review

Dopamine Pathways

  • Meso-cortical – Negative Symptoms - 5’s (Affect, Anhedonia, Attention, Alogia, Avolition, Associability}
  • Meso-limbic – Positive Symptoms - Delusions & Hallucinations; Tuberoinfundibular; Hormonal (Prolactin) & Nigrostriatal - Movement

2 Pathways with Unidentified Function

  • Incerto-Hypothalamic - Circadian
  • Medullary Pariventricular - Sexual Expression


MOVEMENT DISORDERS – associated with the old typicals this is the order they would get it

Dystonias in days

Akathisia in weeks

EPS in months

Tardive Dyskinesias in years



Dystonias (Medical Emergency): Slow, sustained, involuntary muscular contractions; Whole Body or Individual Parts and Difficulty Breathing (least recognized)

Akathisia Greek-German-English: “restlessness” forgot the physical in translation – Mental & Physical

EPS Extra-Pyramidial Side Effects

Pyramidial System – Takes lead in voluntary movement

Extra-Pyramidial System – Background tone prior to voluntary movement

EPS (Extra-Pyramidial/Extra Parksonian Side effects): Muscle stiffness; Cogwheel rigidity; Shuffling gait; Stooped Posture; Drooling; Pill-rolling tremor; Swallowing impairment &  Masked Expression

Tardive Dyskinesia Tongue thrusting - organ in body most susceptible in affects to Acetacoline; Lip smacking and pursing; Rocking of trunk; Pelvic thrusting; Rotating ankle and legs; Marching in place; Repetitive humming/grunting & Irregular respiration



Used to detect TD and to follow the severity of a patient’s TD over timel


Tardive Dyskinesia Monitoring with continued monitoring

Typicals/Conventionals - 4 Months

Atypicals - 6 Months

Clozapine - 9 Months


Metabolic Syndrome

Definition: Clustering of Metabolic Risks  AKA Syndrome X, CHAOS, insulin resistance syndrome, dysmetabolic syndrome, Reaven’s Syndrome

Increase Blood Pressure

Increase Triglycerides

Insulin Resistance - When cells become numb to the insulin produced by the body, precedes the onset of type 2 diabetes

Obesity (apple shape)

Decrease High-Density Lipoprotein (HDL) cholesterol

Increased Risk of Cardiovascular disease and diabetes

Risk of Metabolic Syndrome


  • Clozapine (Clozaril®)
  • Olanzapine (Zyprexa®)


  • Risperdal®/Invega®
  • Quetiapine (Seroquel®)


  • Ziprasidone (Geodon®)
  • Aripiprazole (Abilify®)

CLUE! “I’m always hungry! I’m never full!” Check the med!


Lurasidone (Latuda®)

FDA Approved for: Schizophrenia (October, 2010); Bipolar-Depression (July, 2013) & Schizophrenia, Adolescents (ages 13-17, January 2017, six week study)

Mechanism of Action: Combined Blockade of D2 and 5-HT2 receptors (5- HT > D2); Low affinity for histamine receptors; No activity at cholinergic receptors & Moderate receptor affinity for α1 receptor

Dosage 40 – 160 mg day


Asenapine (SAPHRIS®)

FDA Approved for: Acute Treatment of Schizophrenia (August, 2013) & Acute Treatment of Manic and Mixed Episodes associated with Bipolar I in adults as monotherapy 2013)

Mechanism of Action: Combined Blockade of D2 and 5-HT2 receptors; Affinity for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT6, 5-HT7, α2B, & D3; Moderate receptor affinity for Histamine & No affinity for ACh


Third Generation

Aripiprazole (Abilify®)

FDA Approved for: Schizophrenia & Schizophrenia Maintenance; Acute mania/mixed mania; Bipolar Maintenance; Depression (adjunct) & Autism-related irritability in children ages 6 to 17

Mechanism of Action: Partial Agonist at D2 receptor; Lowest discontinuance rate, side effects

FDA Warning – 5/03/2016  “Compulsive urges to gamble, binge eat, shop, and have sex have been reported with the use of antipsychotic drug aripiprazole (Abilify®, Abilify Maintena®, Aristada®, and generics)”  “Uncontrollable urges were reported to have stopped when medicine was discontinued”  Rare, can affect anyone who is taking med


Brexpiprazole (Rexulti®)

FDA Approved for: Schizophrenia; Adjunctive therapy to antidepressants for MDD

Mechanism of Action: SDAM Serotonin/Dopamine Agonist Modulator (partial agonist 5-HT1A & D2; 5-HT2A antagonist); Poor CYP2D6 metabolizers have 4.8 fold increase active drug exposure & Pregnancy Category Unassigned

Black Box: Dementia-Related Psychosis; increased risk of suicide in children & young adults



Cognitive Remediation Therapy

Teaches cognitive skills of memory, cognitive flexibility, and planning through positive reinforcement; Teaches self-monitoring; Improvement after 6 months


New Approach Advised to Treat Schizophrenia

Landmark Government Study - Most Rigorous to Date - “Alternative treatment program as a whole led to better outcomes.”  Kane, J.M., et al. (2015). Comprehensive versus usual community care for first-episode psychosis: 2-Year outcomes from the NIMH raise early treatment program. American Journal of Psychiatry, published on line.


Sleep Disorders - Hypnotics/Sedatives

Symptom: Insomnia

“Rule Out” Insomnia Due to Physical Disorder

  • Gastro-esophageal Reflux Disease (GERD)
  • Hyperthyroidism
  • Periodic Leg Movement Disorder or Restless Legs Syndrome
  • Pain Syndromes


Mental Health Disorders with Sleep-Related Symptoms



Post-Traumatic Stress Disorder




Traumatic Brain Injury


Sleep & Circadians

You have 8 chemical bodies in a 24 hour period

Circadian, entrainable oscillation 24-26 hours cycle

Infradian, > 1 Circadian - Menstrual Cycle

Ultradian, < 90 – 120 minutes - This is the sleep cycle 45 min to deep sleep 45 min to light sleep with Blood Circulation, Pulse, Heart Rate; Urination & Bowel Activity; Appetite and Nostril Dilation


Sleep Stages

Stage 1: 1-5 Minutes per cycle, easily awakened

Stage 2: Light sleep, 50% of healthy adult sleep - Spindles & k-complexes (necessary for learning); Heart Rate decreases; Body Temperature decreases & Eye Movements Completely STOP

Stage 3: First stage of deep sleep - Blood Pressure Drops; Muscles Relax & Breathing Slows

Stage 4: Deepest, Most Restorative Sleep - More Relaxed; Growth hormones released & 50% Delta Waves


REM Sleep

Entered/Exited through Stage 2:  25% of healthy sleep is REM sleep; 50% of infant sleep is REM sleep; No Voluntary Muscle Movement (muscle atonia); Blood Flow increases by 50%-200%; Sexual arousal increased & Nervous System Increases Activity

NO REM Sleep While Sitting Up! So get Gerd Patients to at least sleep at 45 degrees to get REM sleep

REM cycles throughout the night

  • Increases amount of REM throughout night
  • As REM increases, deep sleep stages decrease
  • Slow Wave sleep first 1/3 of night
  • REM sleep predominates last 1/3 of night
  • After Age 65, REM sleep Decreases

REM Sleep & Neurotransmitters

During REM:

  • 5-HTSeratonin and NE norepinephrine are not secreted
  • DA dopamine activated
  • ACh Acetylcholine activated - Good night’s sleep increases learning


Hypnotics/Sedatives use for Sleep Disorders


Chloral Hydrate


“Non-benzo” benzodiazepines (Z-Drugs):

  • Zaleplon/Sonata®
  • Zolpidem/Ambien®
  • Eszopiclone/Lunesta®

Tricyclic Antidepressants

Atypical Anti-Psychotics

Sedating Anti-histamines


Melatonin Special Precautions

Bleeding Disorders



High Blood Pressure

Seizure Disorders

Transplant Recipients


FDA-Approved Treatments for Insomnia

Benzodiazepines – Allosteric Modulators of the GABA-A Chloride Ionophore

  • Temazepam (Restoril®)
  • Flurazepam (Dalmane®)
  • Triazolam (Halcion®)
  • Quazepam (Doral®)
  • Estazolam (Prosom®)

Melatonin-Receptor Agonists

  • Ramelteon (Rozerem®)
  • Tasimelteon (Hetlioz®)

BZD1-Receptor Agonists

  • Zolpidem (Ambien®)
  • Zaleplon (Sonata®)
  • Eszopiclone (Lunesta®)

Histamine Antagonists

  • Doxepin (Silenor®)
  • Diphenhydramine

Orexin Receptor Antagonist

  • Suvorexant (Bellsomra®)


The Zzzzz-Drugs


  • Zolpidem (Ambien®) – t ½ = 2.5 hrs.
  • Intermezzo® (sublingual zolpidem)
  • Zaleplon (Sonata®) – t ½ = ultra short 1 hr.
  • Eszopiclone (Lunesta®) – t ½ = 6 hrs.

Mechanism of Action: Binds to Alpha 1 isoform

Special Note: Ramelteon (Rozerem®) - Melatonin1 and Melatonin2 Agonist


Tasimelteon (Hetlioz®)

Melatonin-Receptor agonist @ MT1 & MT2

First/Only FDA approved treatment for Non-24-Hour Sleep-Wake Disorder (Non-24)

Non-24: Neurological sleep disorder in which a person’s sleep/wake cycle less than24 hours. Unable to adjust sleep-wake cycle to the length of the day, and sleep time progresses around the clock

Side Effects: Headache, increased alanine aminotransferase (ALT measured to

determine liver health), nightmares, unusual dreams, upper respiratory or urintary tract



Suvorexant (Bellsomra®)

Orexin Receptor Antagonists

Blocks neuropeptides Orexin A and B from binding to OX1R and OX2R

Blockage = suppression of wakefulness & Appetite

NOTE: Orexin A and Orexin B receptors stimulate appetite

Abuse Potential – Low but PRESENT!


Orexin (aka Hypocretin)

Neuropeptide – Small protein-like molecules used by neurons to communicate with each other

Regulates: Arousal; Wakefulness & Appetite

• Cataplexy – most common form of narcolepsy – brief loss muscle tone resulting from lack of orexin in brain


Behavioral Strategies to Reduce Insomnia

Exercise: Exercise 20-30 Minutes a Day &  Exercise about 5-6 hours before bedtime

Avoid caffeine, nicotine, & alcohol

Utilize deep breathing & relaxation exercises

No TV, No iPad, No iPhone, No i-Screen anything

Control room temperature – less than 70 degrees

Sleep until sunlight!


Tetrad of Narcolepsy

1. Sleep Paralysis (temporary inability to move or speak while falling asleep or upon


2. Hypnagogic hallucinations – when going to sleep

3. Attacks of Sleep

4. Cataplexy-lose muscle control