Psychopharmacology Test 3

pSY 4050

Symptoms of Bipolar Disorder/ Types of Bipolar Disorder

• Combination of depressive and manic episodes

• Split into Bipolar 1 and Bipolar 2

Bipolar I

• Atleast one manic/mixed episode

• Minor or major depressive episodes often present

• May have psychotic symptoms

Bipolar II

• One or more major depressive episode

• One or more hypomanic episode

• No full manic or mixed episodes

Mania

• Increased energy

• Increased activity

• Changes in mood

Hypomania

Mild to moderate mania

Considerations for medications for Bipolar

Severity of Manic/Mixed episode

• Less severe (Hypomania) - lithium, valproate, or antipsychotics

• Mixed (Mania) - lithium less effective

• More severe - combination

Rapid-cycling

• Acute response is comparable while chronic response is lower

• Atypical antipsychotics may be preferable

• Antidepressant meds may increase cycling

Euthymia

A stable, tranquil mental state or mood that is neither manic nor depressive.

Mood Stabilizers (types of drugs in this category, potential mechanisms of action)

• Category name for drugs that effectively treat symptoms of bipolar disorder

• Composed of minerals, anticonvulsants, and antipsychotics

• MoA currently unknown

  • neuroprotection/neurogenesis hypothesis

  • second-and-third messenger systems

Lithium (pharmacokinetics, pharmacodynamics, history, side effects)

Mineral for mood stabilization

• Alkali matal

• Historically a common first choice

• 18-24 hour half-life, no metabolism just excretion

• Narrow therapeutic range

• Side effects: GI reactions, weight gain, dermatological reactions, thyroid/kidney function, neurological effects

Anticonvulsants for bipolar disorder (examples, MoA, side effects)

• Tegretol, Trileptal, Depakote, Lamictal

• MoA: Sodium channel blockers, second messanger systems

• Side effects: GI reactions, dermatological reactions, sedation, cognitive deficits, potential for increased suicidality

Atypical antipsychotics for bipolar disorder

Designed to treat psychotic symptoms associated with disorders like schizophrenia

• Can be used to treat acute mania

• May also be used to reduce relapse rates

• Omega-3 Fatty acids (Fish oil pills) may prevent bipolar disorder symptoms but this is DEBATED!

Omega-3 Fatty Acids

• Found at high levels in fish and some plants

• May act to prevent polar disorder

• May be used in combination with other drugs to reduce relapse rate

• Effectiveness is currently debated

Symptoms of schizophrenia

Positive: (adding things)

• hallucinations

• delusions

• confused thoughts & speech

• trouble concentrating

• psychomotor agitation or retardation

Negative: (taking things away)

• flat effect

• anhedonia

• withdrawal

• lack of motivation

• lack of attention

Types of Schizophrenia

• Paranoid

• Disorganized

• Catatonic

Neurotransmitter theories of schizophrenia (support for each)

Dopamine Theory

• abuse of stimulants (e.g. amphetamine) increases synaptic dopamine concentration and produces schizophrenic-like symptoms.

• Dopamine receptor antagonists produce some alleviation of symptoms

Serotonin Theory

• Some psychedelic drugs like LSD are serotonin agonists and also produces hallucinations/altered perceptions.

• Some 5HT2 receptor antagonists reduce symptoms

Glutamate Theory

• Some psychedelic drugs like PCP or ketamine are gluatamte antagonists and result in schizophrenic-like symptoms

• Excessive glutamatergic activity may cause excitotoxicity to nearby neurons causing damage or cell death.

Grey and white matter loss in schizophrenia

Accelerated, progressive gray and white matter loss, particularly in early illness stages and during adolescence, with abnormalities often present at onset. Key findings include structural deterioration in the frontal, temporal, and parietal lobes, leading to reduced volume and altered network connectivity.

First-gen antipsychotics

ex. Haloperidol (Haldol), Chlorpromazine (Thorazine)

Pharmacokinetics

• oral bioavailability is low/variable

• long half-life (20-40hrs)

• many have active metabolites

Pharmacodynamics

• most useful for treating positive symptoms

• primary MoA– D2 receptor antagonists

• secondary MoA– block acetylcholine, histamine, and NE receptors

Side effects

• some sympathetic nervous system effects

• memory deficits

• hypotension

• sedation and weight gain

• hormone dysregulation

• motor impairments (akathisia: neuropsychiatric movement disorder characterized by intense, subjective inner restlessness and a compelling, uncontrollable need to move., dystonia: neurological movement disorder characterized by involuntary muscle contractions, causing repetitive or twisting movements and abnormal postures)

Second-gen antipsychotics

ex. Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seoquel), Aripiprazole (Abilify)

Pharmacokinetics

• relatively long half-life, but varies depending on individual drug (9-40hrs)

• several have active metabolites

• dosage varies widely on an individual basis

Pharmacodynamics

• better at treating negative symptoms than first gen

• primary MoA– D1 antagonist and 5HT2 antagonist

• secondary MoA– varied effects on D2, 5HT7, histamine, acetylcholine, and adrenergic receptors.

Side effects

• weight gain

• diabetes/hyperglycemia

• cardiac abnormalities/cardiac arrest

• reduction in white blood cell count

• motor impairments

New-gen antipsychotics

• Cobenfy (Xanomeline-trospium chloride)

• MoA:

  • Xanomeline: Agonist for muscarinic acetylcholine receptors M1/M4

  • Trospium: Peripheral muscarinic antagonist (Not crossing BBB)

• M1M4 regulate DA release in cortical and subcortical regions

• Improves positive, negative and cognitive symptoms

• Trospium reduces GI effects of xanomeline

Side effects

• GI effects

• Hypertension/tachycardia

• Renal or hepatic considerations

Addiction

A primary, chronic disease of brain reward, motivation, memory, and related circuitry

Use

repeated use of alcohol, illicit drugs, or misuse of prescription drugs with or without negative consequences

Abuse

continued use of alcohol, illegal drugs, or misuse of prescription drugs with negative consequences

Dependence

state of sustained and compulsive use that includes a need to avoid withdrawal

Withdrawal

negative physical and psychological symptoms following cessation of long-term drug use

Tolerance

reduced reaction to a drug following long-term use

DSM-5 criteria for Substance Use Disorder

DSM-5-TR defined substance dependence and substance abuse separately,

DSM-5 combines under new title

Specific for each substance (e.g., alcohol use disorder)

omits caffeine

Has a separate behavioral addiction category

Controlled substance schedules

Schedule 1

• no accepted medical use

• high potential for abuse

ex. heroin, LSD, ecstasy

Schedule 2

• accepted medical uses

• high potential for abuse

ex. methamphetamines, methylphenidate

Schedule 3

• accepted medical uses

• lesser potential for abuse than 1 or 2

ex. Tylenol (w/ certain level of iodine), ketamine

Schedule 4

• accepted medical uses

• lesser potential of abuse than 3

ex. Xanax, Valium

Schedule 5

• accepted medical uses

• low potential for abuse

ex. Robitussin, OTCs (without prescriptions)

Most commonly used illicit drugs/drugs of abuse

Among people ages 12+; 2024

Marijuana 64.2M

Hallucinogens 20.4M

Rx Opioid Misuse 7.6M

Rx Tranquilizer or Sedative Misuse 4.6M

Cocaine 4.3M

Rx Stimulant Misuse 3.9M

Inhalants 3.2M

Methamphetamine 2.4M

Heroin 556K

Most commonly first used drugs of abuse (Initiates of Substances)

Alcohol, nicotine, and marijuana

Current Trends

• National Survey on Drug use and Health

• Higher illicit drug use

  • primarily fueled by uncreased marijuana use

• Most common in 18-25 yr olds

• Most people begin using in teen years

Dopamine pathways and nuclei that contribute to addiction

Mesolimbic → amygdala (avoidance), hippocampus (seeking), nucelus accumbens (motivation)

Mesocortical → attention

Hypofrontality

hyperactivity of frontal cortex

Dopamine receptor changes during addiction

The brain compensates for these surges of dopamine (caused by drug abuse) by reducing the number and sensitivity of dopamine receptors.

Analgesic

Any drug that provides relief from pain

Nociceptor

Sensory receptor that detects pain signals

Nociception

Pain signaling and detection (acknowledgement)

Neuropathic pain

Chronic pain caused by lesion, dysfunction of nervous system, injury, or infection

Opioids/Opiates

Opioids - Natural, semi-synthetic, and filly synthetic pain medications that act on opioid receptors

Opiates - Specific class of natural pain medication that act on opioid receptors and are derived from the opium poppy plant

Narcotics

Alternative name for opioid pain meds

Pain signaling from periphery to cortex

Ascending pathway: After signaling, sensory neuron sends an action potential through the dorsal root ganglion (DRG), spinal cord, up to the thalamus, then cortex.

Descending pathway: The cortex then sends the signal down to the postaglandias (PAG) (which sends to signaling neurons to the Amygdala), then the RVM, and back down to the spinal cord– depending on what needs to happen.

Histamine: inflammation on skin

Substance P: blood-stream signaling

Postglandias: increases histamine & substance P messages

History of Opioids

Opium is an ancient drug isolated from the dried sap of a poppy seed pod.

• first uses recorded were to treat diarrhea and induce sleep

• 1806 morphine was isolated from opium

• readily available in mid-1800s

• unregulated and abused for many years

Natural, Semi-synthetic, and synthetic opioids

Natural - Opium, Codeine, Morphine

Semi-Synthetic (modified natural substance) - Heroin

Synthetic (fully lab-grown) - Hydrocodone, Oxycodone, Fentanyl, Cerfentanil

Addictive properties of opioids

Opioids trigger the release of endorphins

Opioid Receptors

Mu, Kappa, Delta

• metabotropic, GPCRs

• Gamma & Beta subunits act as ion channels

• Alpha subunit inhibits adenylyl cyclase

• overall inhibitory effect in ascending and descending pathways

Ion channel effects of activation of opioid receptors

membrane hyperpolarization and reduced neurotransmitter release

Pharmacological effects of opioids

• Analgesia (reduce pain)

• Euphoria

• Depression of respiration (breathing slows)

• Suppression of cough

• Sedation and anxiolytics

• Nausea and vomiting

• Gastrointestinal symptoms

• Pupillary constriction

• Endocrine effects

Opioid Classes and Examples

Agonists

• Morphine

• Codeine

• Heroin

• Hydrocodone

• Oxycodone (oxycontin)

• Fentanyl

• Methadone

Partial Agonist

• Byprenorphine (subutex)

Antagonist

• Naloxone (narcan, evzio)

• Naltrexone (vivitrol)

Mixed Agonist/Antagonist

• Buprenorphine/Naloxone (suboxone, zubsolv)

Alcohol metabolism

Pharmacokinetics

• Easily diffuses across GI tract membranes

• Easily crosses BBB

• Primarily metabolized in liver by alcohol dehydrogenase (ADH)

• Sex differences in metabolism

• Average person can metabolize 10-14 mL of alcohol per hour

• zero-order elimination

Pharmacodynamics

Depressant

• Positive allosteric modulator of GABA(A)

  • depressant activity

  • disinhibition in VTA - dopamine release

• Inhibits glutamate receptors (NMDA)

  • depressant activity

Stimulant

• Seems to activate serotonin receptors

  • pleasure effects

• Seems to prompt release of norepinephrine (brain) and adrenaline (pituitary gland)

  • low dose stimulant

  • biphasic effect

Pleasure/Addiction

Alcohol seems to have multiple effects in opioid system

• Increase binding affinity of Mu and Delta receptors

• Elicit opioid release that then binds to opioid receptors

  • partially through the tuberoinfundibular tract (DA)

  • also sees increases in NAc and VTA

• Downstream effects on dopamine– addictive

• pleasure effects

Proof

twice the percentage of alcohol (Ex. 40% = 80 proof)

Behavioral effect (dependent on dose)

Low dose – some stimulant effect

• Increased sociability

• Increased energy

• Increased respiration

High dose – primarily depressant effects

• Decreased respiration

• Sedation

• Cognitive deficits

• Motor impairments

• Speech impairments

• Decrease in body temperature

• Dinhibition

• Sexual dysfunction

Measured in Grams%

Legal limit: 0.08%