Psych 127b - Exam 2 (Karlsgodt)

Depressants: Alcohol

- Main difference from other depressants - primarily recreational rather than medicinal - Absorption: Easily and rapidly absorbed from entire GI tract, Time to maximal blood concentration 30-90min, Evenly distributed throughout body, BBB very permeable (so is placenta) - Metabolism: In stomach and in liver, Women have less metabolic enzymes in stomach

Liking

- Medicated by dopamine: Dopamine loss renders drugs ineffective at supporting behavior; Drugs that block dopamine receptors also attenuate the acquisition of drug taking in animals - Establishes and supports drug-associated behavior early on - Roots of Positive Reinforcement: drugs converge onto dopamine systems (Amphetamine/methamphetamine acts by stimulating dopamine terminals to release more dopamine into the nucleus accumbens) - Some aspects require learning: Drug-taking, Incentive significance of drug associated cues (pipes, spoons, syringes, etc) , Avoidance behavior for the drugs that induce somatic withdrawal - Alterations in reward function: Reward-deficiency syndrome, reduced activity in the reward pathway can trigger drug seeking behavior, reduced activity can come through 3 primary pathway: genetics, drug use, cessation of drug use

Psychostimulants: Methamphetamine

- Meth differs because it has a methyl group - more readily passes BBB; more resistant to breakdown - Meth - can be synthesized from readily available chemical (greater potential negative impact o society) - Long term toxicity effects similar to cocaine (psychosis, paranoia, violence)

Cannabinoid: Opioid

- Morphine, vicodin, oxycodone, fentanyl, heroin, opium - Work on the body's own opioid system (Natural opiates - enkephalins and endorphins - function as neurotransmitters; Receptors: me, kappa, delta) - Effects - euphoria, drowsiness, slowed breathing, analgesia (Powerful for use in pain management, medical treatment (surgery)) - Withdrawal - nausea, vomiting, chills, muscle aches, diarrhea, insomnia

Cannabinoids: Routes of administration

- Most common method inhalation - Sometimes consumed as food (brownies, gummy bears) - CB1 receptors - high density in regions associated with executive functions (prefrontal cortex) - Endocannabanoid system (neural system on which cannabis works) has roles in brain development, including in adolescence Psychoactive Effects (varies by individual): - Altered states of consciousness, euphoria, relaxation or stress-induction - Increased appreciation of humor, music, or art - Introspection - Increased sensuality, awareness of sensation, and increased libido - Disruptions of memory -Paranoia or anxiety Side Effects: - Increased heart rate - Dry mouth - Reddening of eyes - Muscle relaxation - Sensation of heat or cold (especially hands and feet) - Reduction in motor activity

Psychostimulant: Caffeine

- Most popular, most widely consumed drug worldwide - Rapidly absorbed orally (sig blood levels in 30-45 min, peak in 2 hours) - Effects: Slight stimulant (heart rate, vasodilation peripherally, but vasoconstriction in brain) - Adenosine receptor antagonist in CNS (Normally adenosine works on a number of receptor systems to produce sedation, regulate oxygen delivery, dilate blood vessels, etc; Blocking adenosine receptors increases NTs, including primarily DA and 5-HT) - Negative effects at high doses (500-1000mg/day) - 1 50z cup of coffee = 100mg; 1 12 oz soda = 40mg

Tension Reduction Theory (in alcohol)

- Motivation to drink is to reduce tension - Alleviation of tension becomes reinforcer - But, not all people report reduction in tension (some, increase) - Better at reducing tension if there is also distraction (e.g. drinking buddies)

Learned Helplessness

- People are more anxious and depressed when they feel they have no control over stress - Depression can follow hopelessness about coping with life events - Seems that negatively cognitive styles precede and are a risk factor for depression (psychological vulnerability) *Depressive attributional style*: *Internal*: attribute bad things to a personal failing *Stable*: even if bad events pass, still think it was your fault *Global*: attributions span across a number of different issues

Heritability of Bipolar Disorder

- Population risk: 1% - 2% - Risk for 1st degree relatives: 9% - MZ twin concordance: 40% - 45% - Heritability : 80% - 85%

*Dopamine and Reward*: Associated Systems (Why are some drugs addictive , and some not?)

- Released primarily into: Basal ganglia (striatum); Frontal lobe - Nigrostriatal System: Role in movement - Mesolimbic System: (Role in reinforcement/reward) - projects to nucleus accumbens (NAcc), cortex, hippocampus - Mesocortical system: (role in short-term memory, planning, and problem solving)

Oral administration

- Requirements for being effective: Be stable in stomach fluid, Enter intestine, Penetrate lining of intestine, Pass into blood stream - Usually absorbed in 1-3 hours (slow) - Limitations (Unknown dosage) - Pills, liquid medicine

Genetic Aspects of Addiction: What does it mean that it is heritable?

- Shouldn't categorize as being so different from things like schizophrenia, bipolar, and other psychiatric disorders with less stigma: Cocaine use disorders 72%, Alcohol dependence 56%, Sedative use disorder 51%, Cannabis use disorder 48%, Stimulant use disorder 40% - Determining specific genes might lead to avenues of biologically based treatment

Psychostimulants: Amphetamines

- Sympathomimetic agent - mimic the action of adrenaline on the ANS , affects norepinephrine - Psychological (Vasoconstriction, hypertension, increase heart rate; Restlessness, increased motor activity, agitation, insomnia, loss of appetite) - Increases DA release, blocks DA reuptake, and makes reuptake transporter work backwards, may inhibit MAO - Strong impact on DA release

Serotonin Neurotransmission

- Synthesized from amino acid, trytophan - Reuptake by a specific serotonin reuptake transporter (molecular target of a cluster of antidepressant medications (SSRIs), futher breakdown by monoamine oxidase (MAO) - Trytophan - > 5-HT -> diffuse or reuptake -> MAO -> 5-HIAA

Treatment for Acute Depressive Symptoms

- Treated with SSRIs, MAO-Is, ECT or TCAs - SSRIs are typically first pass treatments - Depression with anergia (abnormal lack of energy) is generally tackled with MAO-Is - TCAs (and possibly SSRIs) are problematic in patients at high risk for suicide - Some standard antidepressants may even trigger a manic episode, so have to be careful

Pure Norepinephrine Reuptake inhibitors are also antidepressant

- Tricyclic drugs, as a group, have the ability to block both serotonin and norepinephrine reuptake -But some are pure norepinephrine reuptake inhibitors, and yet, they work

Withdrawal

- Very severe syndrome - Deleriem Tremens (DTs): auditory, visual, tactile hallucinations - Extreme anxiety ( want to jumps out of skin) - Panic attack - Glutamate adaptation (Cannot stop cold turkey, Too much excitation = seizures, Potentially fatal , Need medical supervision: Benzodiazepines - to balance out GABA)

Cannabinoid: Marijuana

- Withdrawal symptoms: irritability, anger, depressed mood, headaches, restlessness, lack of appetite, and cravings for marijuana - Symptoms first appear in serious habitual used within the first 8 hours - Most noticeable during the first 10 days , but may last as 45 days - The withdrawal from marijuana is identifiable ny behavioral and emotional distress Prevalence: - 14.6 millions americans used in the past month - About 35% of users qualify for a substance use disorder - Adolescent users more likely to develop a disorder There are many kinds of cannabinoids , strains vary: - THC - major psychoactive ingredient CB1 Receptors - CBD (cannabidiol), not hallucinogenic, may be anxiolytic

Learning about pathophysiology from treatment

- e.g. the tuberculosis drug iproniazid - studies in the 1950's (which predated knowledge of the mechanism of action) showed that it had mood elevating effects - Iproniazid is a monoamine oxidase inhibitor (MAOI) -What does MAO do? What is the net effect of inhibiting it? (makes the enzyme that breaks the MAO break down less

DELETE

-Depression runs in families - From twin, family, and adoption studies estimated 40-50% heritable - Heritability higher in more severe cases (3 or more MDEs) - Heritability is substantially greaters for females vs. males in some studies

Co-Morbid Disorders (6)

1) Substance Abuse Disorders 2) All anxiety disorders (particularly GAD) 3) Anorexia Nervosa - An eating disorder causing people to obsess about weight and what they eat 4) Bulimia Nervosa - A serious eating disorder marked by binging, followed by methods to avoid weight gain 5) Borderline Personality Disorder 6) Psychotic Disorders

Suicide (7)

1) Suicide is a concern not just in mood disorders, but other mental illness as well 2) 11th leading cause of death in the US 3) Frequently is rising among young people, it is 3rd most common cause in teenagers (being unintentional injury, accidents, and homicide) 4) *Suicidal ideation*: thinking seriously about suicide, with ot without intent 5) *Suicidal plans*: formulation of specific plan 6) *Suicide attempts*: the person survives 7) *Suicide completion*: the person does not survive

Mortality and Depression (2)

1) Up to 15% die by suicide (DSM-4) 2) 4 fold increase in death rates of depressed individuals after age 55 (DSM-4)

What does feedback look like in a synapse?

Autoreceptors: stimulated by the same neurotransmitter being released, cause cell to be less likely to fire (inhibitory), acts as a feedback loop (like HPA Axis)

Monoamine Oxidase Inhibitors and it's problems

Class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A and monoamine oxidase B. They are best known as powerful anti-depressants, as well as effective therapeutic agents for panic disorder and social phobia Principle Problems: - General side effects - Liver toxicity weight gain - "Cheese" effect (need for dietary restriction): MAO (chocolate, aged cheese, alcohol) have hypertensive effect via it's agonist effects on other monoamines

Personality Disorder Clusters: Cluster A, Cluster B, Cluster C

Cluster A: odd/ eccentric behavior, ranging from distrust. Suspiciousness to social detachment; Paranoid; Schizoid; Schizotypal Cluster B: Tendency to be dramatic/ emotional/ erratic; Histrionic; Narcissitic ; Borderline Antisocial Cluster C: Anxiety and fearfulness; Avoidant dependent; Obsessive-compulsive

What is a Personality Disorder?

DSM-5 Personality Disorder General Criteria: -An enduring pattern of inner experience & behavior that deviates markedly from expectations of the individual's culture in 2 or more of the following areas and leads to distress or impairment (inner experience = thought and feelings) - Cognition - Affect - Interpersonal functioning - Impulse control Prevalence of Personality Disorders - About 2.5% - 10% of the general population - Rates are higher in inpatient and outpatient settings

Paranoid personality disorder

Deeply rooted distrust and suspiciousness of other people without justification; interpret actions of others as meant to harm or trick - Clinical characteristics: Distrust when others would agree suspiciousness is unfounded; Everything seen as personal attack; Preoccupied with doubts about others loyalty; Argumentative, hostile, combative; Social detachment/ isolation because are reluctant to confine or trust; Grudges - Treatment options: Few seek professional help on their own, Treatment focuses on development of trust, Cognitive therapy to counter negative thinking, Lack of good outcome studies - Differs from psychosis: No hallucinations; Beliefs might look like delusions but individuals are more likely to have some awareness that the paranoia is excessive

How does the neuron know when to stop releasing?

Feedback from autoreceptors! like the HPA Axis

Genetic Vulnerability: serotonin Transporter Gene 5-HTTLPR

Genes related to the neurotransmitter serotonin interact with life effects to affect risk for depression - short and long variants are most studied - long allele associated with higher serotonin transporter mRNA transcription & short allele lower transcription - Short allele associated with depression in some, but not all studies

Monoamine Hypothesis

Hypothesis: Monoamine Levels are Too Low in depression A monoamine oxidase inhibitor reduces depressed mood We may infer from this that low monoamies levels cause depressed mood Increasing synaptic serotonin and norepinephrine can increase mood and decrease anxiety However, 30% of all individuals won't respond adequately to monoamine-based drugs; "therapeutic lag"

St Johns Wort (plant)

It is believed to be a medicinal herb with antidepressant activity, although high-quality clinical evidence for such effects is limited. - May be somewhat effective for mild-moderate depression in the laboratory (Studies highly variable; real life quality of product highly variable) - Multiple effects (Inhibits reuptake of NE, 5-HT, GABA) - Can interact with many other medications (Can be dangerous with no supervision) - Unregulated dosage

Mania

Mania is a facet of type I bipolar disorder in which the mood state is abnormally heightened and accompanied by hyperactivity and a reduced need for sleep. By contrast, hypomania (often described as "mania-light") is a type II bipolar disorder which neither has the range nor severity of symptoms that classic mania has - 20% of persons with history of mania report no depressive episodes - 27% of bipolar I no MDE - Controversy over whether this is stable over the lifespan - Creativity and Mania (e.g. Vincent Van Gogh; creativity unlikely to occur during manic episodes, but possibly by hypomanic; unaffected relatives more likely to be creative

Depression and Anxiety

Mood disorders that are known as the "common cold" of mental illness. Prevalence: major depression 30% > Generalized Anxiety Disorder 22% > both 16% > Bipolar Disorder 1%

Cycle

Phenomenology --> treatment --> pathophysiology --> etiology - It is notes that certain phenotypes respond to particular interventions - The mechanisms of action of those treatments are revealed and used to infer pathophysiology - The pathophysiology is studies to reveal possible causes

Bipolar I Disorder

Presence of 1 manic episode in one's lifetime. (More severe than Bipolar II (hypomania) 1) Specify nature of most recent episode e.g. manic, major depressive episode 2) specifiers for current episode: mild, moderate, with psychotic features, over 50% experience psychotic features at some point in lifetime 3) course specifiers: seasonal pattern; rapid-cycling (at least 4 mood episodes in 12 months)

DSM-V Criterion for substance use disorder (11)

Problematic pattern of substance use, leading to clinically significant impairment or distress, as manifested by at least 2 of the following ,occurring in the same 12 month period: 1) The substance is often taken in larger amounts or over a longer period than was intended 2) There is a persistent desire or unsuccessful efforts to cut down or control substance use 3) A great deal of time is spent in activities necessary to obtain or use the substance ,or recover from its effects 4) Cravings, a strong desire to use 5) Recurring use resulting in failure to fulfill major obligations at work, school, home 6) Continued despite knowledge of having persistent or recurrent social or interpersonal problems 7) Important social, occupational, or recreational activities are given up or reduced 8) Physically hazardous (like driving) 9) The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem 10) Tolerance, as defined by either of the following: A need for markedly increased amounts of the substance to achieve intoxication or desired effect. OR Markedly diminished effect with continued use of the same amount of the substance 11) Withdrawal, as manifested by either of the following: The characteristic withdrawal syndrome for the substance OR The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms.

Synapse

Released neurotransmitters then have an excitatory or inhibitory effect on the post-synaptic membrane, making the cell they connect to either more or less likely to fire/signal

Therapeutic Lag-Autoceptor Desensitization

Some change in the brain in response to chronic, but not acute, antidepressant treatment leads to clinical effects; other genomic changes caused by chronic drug treatments -Autoreceptors are generally opposing the beneficial effects of MAOI- and SSRI-like drugs -But these autoreceptors are desensitized as a function of chronic drug treatment -Therefore, their feedback inhibition is diminishing and the ability of the therapeutic substances to increase synaptic levels of the transmitter is growing as a function of chronicity

Needing

Sometimes physical dependence occurs which results in a somatic state which supports avoidance behavior Tolerance and Dependence: Pharmacological Criteria - Tolerance - a state in which an organism no longer responds to a drug - Dependence- a state in which an organism only functions normally in the presence of a drug

Wanting

Stimuli associated with drug intake provoke the desire for drugs and facilitate the instrumental drug-taking act Why does intake escalate: - Liking increasing duration of intake, several things occur - At the behavioral level, drug effects are changing (sensitization or tolerance - Use patterns may be changing (escalation) - At the neuronal level, physiological effects of the drug may be altered (Neurochemical or molecular changes, Rewarding effects decrease (tolerance), Trying to take more to get same effect - Cues associated with drugs evoke craving: Showing cocaine addicts pictures of things that remind the of cocaine (syringes, white powder, etc) dramatically increases blood flow in the amygdala - Reinstatement: Cues associated with drugs can reinstate drug-seeking behavior, even when it has been extinguished

Disability-adjusted life year

Sum of life years lost due to premature mortality and years lived with disability adjusted for severity

If post-synaptic neurons need to be sensitive to multiple inputs from the same pre-synaptic neuron (temporal summation), what needs to happen so they can tell individual stimuli apart?

The body does a clean up of neurotransmitters to differentiate between signals

Personality Disorder

The nature of personality disorders: - Often thought to begin in childhood - Enduring, inflexible predispositions (run a chronic course) - Consistent across a range of situations - Maladaptive, causing distress and/or impairment - High comorbidity - can have multiple, from different clusters - Poorer prognosis - Ego-syntonic: Unlike other disorders, often feel consistent with one's identity; patients don't feel that treatment is necessary 10 specific personality disorders organized into 3 clusters

Types of dependence: (2)

The need for the presence of the drug in order to function normally 1) *Physiological dependence*: The development of tolerance to a substance or the presence of withdrawal when they stop taking that substance abruptly 2) *Psychological dependence*: Forceful, subjective urges to use substances often as a means of relieving negative mood states such as craving, irritability, insomnia, depression, or anorexia

Substance Use Disorders: Pharmacokinetics

The process by which drugs are absorbed, distributed within the body, metabolized, and excreted Routes of administration -*A*sorption, *D*istribution in the body, *M*etabolism/inactivation, *E*xcretion

The newest generation of antidepressants

The so-called "dual mode" antidepressants - specific serotonin/norepinephrine reuptake inhibitors (SNRIs) - luvox (fluvoxamine) - effexor (vanlafaxine) - cymbalta (duloxetine)

Beck's Cognitive Model of Depression

*3 levels of thinking*: 1) Depressive self-schemas: themes of inadequacy, failure, loss, and worthless (e.g. i am unloveable) 2) Maladaptive beliefs/assumptions: "if X doesn't love me, that means I am not a loveable person" 3) Negative automatic thoughts: day to day thoughts " he doesn't love me" *Beck's Depressive Cognitive Triad*: negative perceptions of self, personal world, future (Dysfunctional attitudes or negative outlook present all the time) ; we can see these effects in learned helplessness: learned that you can't control anything that is happening in your life

Acute Grief, Integrated Grief, Complicated Grief

*Acute Grief* (first 6-12 months): sadness, crying intermixed with periods of positive feelings, struggle to accept reality of situation, feelings of disconnection, frequent thought of loved one, may wish to join them, somatic disturbances (sleep, appetite, fatigue, restlessness) *Integrated Grief*: feel like have adjusted to loss, regain capacity to function, experience joy, will still have feelings of sadness/longing, still have thoughts of loved one but are not dominating, may be surges of grief (anniversaries) *Complicated Grief*: Intense feelings of acute grief persist, excessively concerned of focused on circumstances of and consequences of the death, difficulty accepting death,, excessive avoidance of reminders, social disruption (confusion about role in live, not pursuing interests)

Agonist vs Antagonist

*Antagonist*: a drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell; blocks post-synaptic receptor, speed up the breakdown of NT in the synapse, stimulate the autoreceptor *Agonist*: A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell; stimulate post synaptic receptors, block re-uptake, slow or stop the breakdown of NT in the synapse

Persistent Depressive Disorder (5)

*Formerly Dysthymia 1) Depressed mood for most of the day, more days than not for 2 years 2) Fewer and less severe symptoms than MDE (2 or more symptoms - they stick around longer): Poor appetite or overeating insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions, feelings of hopelessness 3) never been without symptoms for 2 months 4) Onset: early 20's 5) Early onset: before 21 (greater chronicity, poor prognosis, stronger familial component)

Grief and Depression, and it's differences

*Grieving is a normal, healthy reaction to a significant loss* - Many symptoms are the same as depression, but it can be difficult to disentangle - Depression often follows loss; grief persists for 1-2 years *Differences*: 1) Grief involve waves of painful feelings intermixed with positive memories; Major Depressive Disorder typically almost constantly negative 2) Self esteem preserved in grief; Major Depressive Disorder have feelings of worthlessness, self loathing - Depressive feelings are apart of grief, but want to avoid incorrectly labelling a normal process as a disorder

*Depressive Disorders*: Major Depressive Disorders, Onset, and Sex Differences

*Major Depressive Disorders*: does not involve mania or hypomania. Single episodes are rare (85% have another); Recurrent if 2 or more episodes separated by at least 2 months and the typical duration of an episode can be 4-5 months *Onset*: Risk low until early teens, then increases (mean age 18.3-30~years) *Sex Differences*: Females are twice as likely to have major depression, however the gender imbalance disappears after age 65

Neurotransmitter Dysregulation

*Poor Neurotransmitter Activity Linked to Mental Illnesses* - Many Neurotransmitters implicated in disorder - Key players: dopamine, serotonin, GABA, Substance P, Norepinephrine

Mood Disorders: Social and Cultural Dimensions

*Social Support*: 1) Related to depression: 10% women with a close friend become depressed whereas 37% without a friend did 2) Lack of support: predicts late onset depression 3) Substantial support: predicts recovery for depression (not mania) *Gender Differences*: women have twice the odds ratio of major depressive episode

Pharmacology of Bipolar Disorder

*Treatment of acute mania*: Treatment targeted to the agitation, impulsiveness and euphoria *Treatment of acute depression*: traditional antidepressant interventions (potential for mood destabilization) -Mood stabilization: maintenance of the euthymic state -Treatment of psychotic symptoms - Most bipolar patients are on a collection of medications, usually one or two mood stabilizers, an antidepressants (if necessary), GABA-type drug (for sleep) and (sometimes) an antipsychotic

Biological Treatment

- *Agonist substitution* - give a partial agonist e.g.methadone - *Antagonist* : block the effect of a drug (Ex: naltrexone-opiate antagonist; limited efficacy alone) - *Aversive treatment-counter conditioning*: Make use of drugs extremely unpleasant (Ex: antabuse for alcoholism: makes people feel ill; Initial success but doesn't alter conditions that started and maintained drinking) - *Subjunctive medication*: Cope with withdrawal symptoms (Benzos (valium) : reduce accompanying anxiety; - *Wellbutrin*: curbs craving for nicotine) - Efficacy: Limited when used alone; Better with psychosocial treatment

Psychosocial Treatment

- *Dual diagnosis* - be sure to address any other comorbid disorders - *Inpatient facilities*: Expensive and efficacy is equal to outpatient; Often focused to detoxification, which is only the first step - *Alcoholics Anonymous/ Narcotics Anonymous (12 step)*: Most popular, effective for highly motivated people; Based on a disease model and use of spirituality; Total abstinence; Social support - *Controlled use - moderation management*: Can be beneficial to those capable of using in moderation; People feel like may fit better socially ;Not endorsed by AA - *Relapse prevention*: Learned aspects of dependance; Address distorted cognitions; Identify negative consequences; Increase motivation to change; Identify high risk situations - *Reframe relapse*- failure of coping skills, not person - Prevention

Prevalence and Course of Bipolar Disorder

- 2.1% of population meets criteria for bipolar I or II (1.0% bipolar I ; 1.1% bipolar II) - Age of onset: one large study found 50-60% onset before age 19; 15-28% onset before age 13; earlier age of onset associated with rapid cycling and worse course of disorder

Genetic Aspects of Addiction: Treatment (2)

With a set of disorders that have so many contributing factor, it is almost certain that treatment will also have to be multi-faced 1) Biological 2) Psychosocial

Cognitive Therapy for Mood Disorders

- About 70% of patients get better - Slower than drug treatment in producing initial response (2-3 months vs 4 weeks) - Efficacy roughly equivalent to drug treatment at 6-month follow up - May be better maintenance of treatment gains (lower release rate) than drug treatment after discontinuation - CBT (focus on maladpative thinking, behavioral activation (schedule pleasurable events) - IPT: focused on maladaptive relationships + cognitive processes and also relationship difficulties

Inhalation

- Absorbed quickly because of close connection of blood and lung membranes - More predictable dosage - Fastest onset of effects (Almost as fast as injecting; Filtered through lungs first) - Downsides: non absorbed substances can damage lungs - Smoking

*Nucleus accumbens - ventral striatum* (Why are some drugs addictive , and some not?)

- Heavily implicated in processing of reward cues because it helps process information about rewarding and aversive stimuli - For example: Drug converge onto dopamine systems (Amphetamine and methamphetamine cause DA terminals to release more DA into the NAcc)

Reward-deficiency syndrome

- Hyposensitivity to reward - Reward center is not readily activated by 'normal' life events so they turn to drugs to stimulate this pleasure pathway, especially in times of stress - Dopamine may be the key to this syndrome

Types of Tolerance: (3)

1) *Adaptions* your body makes that changes how drugs have their effects 2) *Metabolic tolerance* develops when repeated exposure to a drug causes the persona's liver to produce more enzymes that are used to metabolize the drug 3) *Pharmacodynamic tolerance* (neuroadaptation) occurs when receptors in the brain adapt to continued presence of the drug by downregulation

Phases of substance abuse (4)

1) Sampling 2) Liking 3) Wanting 4) Needing

What happens to the post-synaptic cell?

- If a neuron gets enough positive (excitatory) input, it will fire and signal to the next cell - If a neuron gets a mix negative and positive input (excitatory and inhibitory) it will come them together and may or may not fire - Cells get input from multiple pre-synaptic neurons: it get lots of excitatory input in a row from one neuron, that can also make it fire (spatial summation)

Injection

- Into muscle (IM), under skin (subcutaneous), in vein (IV) - Precise dosing - IV - one of the fastest speeds of onset of any route (1 min or less; Directly to brain) - Downsides (Less time to respond to reaction or overdose; Needs to be sterile)

Drugs vs. Natural Reinforcers (Why are some drugs addictive , and some not?)

- Addictive drugs have reinforcing effects - Neural mechanisms of these reinforcers effects likely to involve the release of dopamine in the nucleus accumbens which helps process information about rewarding and aversive stimuli - Drugs also can provide alleviation of negative stress (withdrawal , or pre-existing negative feelings) - Natural reinforcers - food, water, sex (Necessary for survival , reproduction) - Drugs tap into existing neural circuitry, but brain may not know the difference 0 thinks it should be repeated - Often more reliable, and powerful, stimulation of the circuitry than natural factors

Sampling

- Before anything else can happen, you have to try it (sample it) - What might impact sampling: Availability, Individual differences, Risk-taking behavior, Pleasure-seeking, Impulsive personality types, Comorbidity with psychiatric disorders, Experience with other substances - Subject either likes the drug or not Dimensions impacting sampling: Genetic variation in the Dopamine D4 receptor (Naturally occurring genetic variation: Personality traits, Substance abuse; Attention deficit/ hyperactivity disorder; Social variation in exposure to drugs (Prerequisite for use, Culture (dry vs wet culture), Media, Peers (especially during adolescence), Family-Decrease in monitoring, Parental involvement protective factor)

Drug Treatments in Bipolar Disorder: Why is it different?

- Bipolar disorder is a bit different than other syndromes because interventions must be targeted to the "state" of the disorder - Treatments for the acute manic and acute depressive states are different (they may provoke one another) - Maintenance therapy is required; drug withdrawal is typically associated with rapid relapse

Psychostimulants: Nicotine

- Caffeine, alcohol, nicotine most commonly used psychoactive drugs (High rate of smoking in many psychiatric population) - Primary administration routes - easily absorbed (Smoking (manner of smoking influences amount of nicotine); Topical (chewing tobacco , nicotine patch) -Acetylcholine receptors: Two main subtypes of receptors: Nicotine, Stimulated by nicotine, At neuromuscular junction (NMJ), Muscarinic (Stimulated nu muscarine) - Nicotine is a potent agonist of the nicotinic receptor. Its effects are all mediated by receptor - In CNS, Ach receptors modulate levels of other NTs (like dopamine) and Ach release enhances memory & concentration - In ANS, Activates sympathetic nervous system - release NE and epinephrine - Agonists: Cardiovascular - increased heart rate, hypertension, vasoconstriction; Digestion, - increase motility; vomiting) - Antagonists: Dry mouth, lack of sweating urinary retention; Vasodilation, hypotension; Can affect both parasympathetic and sympathetic

Topical administration

- Can be through mucous membranes - Absorbed directly into bloodstream - Mucus membranes - Nitroglycerin, sniffing/ snorting drugs, chewing tobacco, squietable nasal decongestants ( Fast (~2 min)) - Skin - smoking or birth control patches (A little bit slower ; long release mechanisms)

Serotonin

- Cell bodies of serotonin producing neurons in brain stem - Release serotonin into the brain - Serotonin controls feedings/satiety, sexual behavior, the sleep-wake cycle and mood regulation - Also called 5-hydroxytryptamine (5-HT)

Psychostimulants: Cocaine

- Comes from coca plant (Peru, Bolivia) - chewed leaves, tea - Modern routes of administration: Nasal (snort), Smoke, Inject Primary Effects: - Short term low dose: Local anesthetic, Physiological (sympathetic system: Vasoconstrictor, Hypertension, Pupillary dilation, motor hyperactivity) - Short Term Psychostimulant properties: Euphoria, giddiness, Powerful reinforcement, increases desire for more - Long term high dose use: Anxiety, sleep deprivation, hypervigilance, paranoia, impulsive, altered perception of reality, Wide range of psychiatric symptoms - Cocaine increases synaptic levels of DA (dopamine) by inhibiting reuptake into the presynaptic terminal - Cocaine also affects 5-HT (serotonin) and NE (norepinephrine) reuptake - Cocaine effects on Dopamine Release: DA levels can be measured in the animal brain by microdialysis; When you measure DA release in the nucleus accumbens and give a rat an injection substantially - Cocaine Infusion in the MR (Bloodflow in the nucleus accumbens)

The Opioid Crisis

- Death from opioid use increasing rapidly (Prescription and non-prescription) - Complicated by need for use of opiates in pain management

Dopamine & Bipolar Disorder

- Dopamine enhanced during mania & diminished during depression - Dopamine agonists (e.g. amphetamine) can trigger mania in non-bipolar subjects & increase manic symptoms in bipolar subjects - Sleep deprivation interferes with normalizing sensitivity of dopamine receptors functioning (10% of non-bipolar individuals experience manic symptoms following sleep disruption)

Inactivation and Excretion

- Enzymes deactivates drugs (liver) - Drugs are eventually excreted (kidneys) - Other excretion routes: skin, lungs, bile - Drug interactions can happen either because of mechanism of action, or competition for metabolic enzymes

GABA, GLUtamate and Alcohol

- Ethanol is GABA-A agonist - prolongs ability to activate receptor (similar to barbiturates and benzodiazepines) - Also NMDA (glutamate) antagonist - Over time, with chronic use, GABA and NMDA receptors adapt: GABA receptors decrease sensitivity (require more stimulation to open), NMDA receptors become more responsive

Electroconvulsive Therapy (ECT)

- For treatment resistant depression - use electrical stimulation to the skull to induce a seizure (although patient is anesthetized and has muscle relaxants) - Often requires continued psychotherapy during and after - Exact mechanisms unknown (new work being done using neuroimaging before and after ECT to determine why it is having its effects) - Side Effects (confusion, memory loss, headache, muscle ache, medical complications from anesthesia, rare heart problems)

Transmitter Inactivation

- Have to clean up the synapse - Once released, transmitters must be inactivated to preserve the discreteness of neuronal signaling (the ability to tell each signal apart) - This involves a number of mechanisms including: transmitter diffusion (when transmitter leaks out the synapse), synaptic catabolism (enzymatic breakdown in the synapse), reuptake (actively transport neurotransmitters back across membrane and followed by recycling or breakdown

*Mood Disorders*: Additional Facts and Statistics (2)

1) *Fundamentally similar in children and adults*: differences depend on development stage; 3 year olds are more likely to have somatic symptoms (when a person feels extreme anxiety about physical symptoms such as pain or fatigue), irritability, and reduced activity 2) *Relation between anxiety and depression*: Most depressed persons are anxious, but not all anxious persons are depressed (some people have mixed depression and anxiety)

The Nature of Suicide: Facts and Statistics (2)

1) *Gender differences*: *males* are 4 to 5x times more often to complete suicide than females ; often choose more violent methods like guns and hanging ; highest rates among men over 65 ; *females*attempt suicide more often than males ; rely on less violent methods like drug overdose 2) *Risk factors of Suicide*: suicide in the family ; preexisting psychological disorder - 60% have mood disorders ; alcohol use and abuse -- 25-50% of suicides ; past suicidal behavior ; experience of a shameful/humiliating stressor or severe event (e.g. failure in school, arrest, rejection by loved one, natural disaster) ; plans and access to lethal methods

Ways of Relating Neurochemical Dysfunction to a Disorder (3)

1) *Observe changes in endogenous neurotransmitter levels/function in individuals with a disorder (relative to unaffected persons)*: levels of 5-HIAA are lower in the cerebrospinal fluid and blood of depressed patients; implies less serotonin so there must be less stuff to break it down 2) *Manipulate the system in normal individual in a way hypothesized to mimic the disorder and determine the consequences*: Depleting trytophan from the diet (reduces serotonin, triggers depressive symptoms); treating organisms with drugs that deplete serotonin depressive symptoms 3) *Determine if effective treatments work through modifications of that neurotransmitter system*: MAO inhibitors are effective antidepressants treatments (attenuation of symptoms (strong placebon effect), prevention of relapse); serotonin specific reuptake inhibitors (SSRIs) are effective antidepressants (both help alleviate mood)

What constitutes a manic episode? (3)

1) A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting as least 1 week (or any duration if hospitalization is necessary) 2) 3 or more symptoms (4 if mood is irritable) need to be present: - inflated self-esteem or grandiosity - decreased need for sleep (e.g. feels rested after only 3 hours) - more talkative than usual or pressure to keep talking - flight of ideas or racing thoughts - distractibility - increase in goal directed activity (either socially, at work, school, or sexually) or psychomotor agitation - excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g. spending sprees, speeding, sexual indiscretions) 3) Mood disturbances causes significant impairment in functioning or social activities or relationships with other or necessitates hospitalization or psychotic features

DSM-5 Criteria for Mood Disorders (9)

1) Depressed mood most of the day, nearly everyday (in children/adolescents can be irritable mood) 2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day 3) Significant weight loss or gain or decrease or increase in appetite 4) Insomnia or hypersomnia every day 5) Psychomotor agitation or retardation nearly every day 6) Fatigue or loss energy nearly every day 7) Feelings of worthless or excessive guilt nearly every day 8) Diminished ability to think or concentrate, or indecisiveness, nearly every day 9) Recurrent thoughts of death, recurrent suicidal ideation, suicide attempt

Heritability of Depression (6)

1) Depression runs in families 2) From twin, families, and adoption studies estimated 40-50% heritable 3) Heritability higher in more severe cases 4) Heritability is substantially greater for females vs males in some studies (65% vs 50%) 5) Early onset tends to be more heritable 6) Having more symptoms tend to be more heritable

Psychosocial Treatments for bipolar disorder (3)

1) Interpersonal and social rhythm therapy (ISRT): regulation of sleep cycles and daily schedules (Increased time in remission) 2) Family-focused treatments: Family tension leads to increased relapse ; Focus on communication skills, psychoeducation, and coping styles) 3) Cognitive therapy

Routes of Drug Administration (4)

1) Intravenous (IV) Injection - inject substance directly into vein. 2) Oral Administration - swallow it Inhalation - breathe vaporous substance into the lungs 3) Topical Administration - administer directly onto skin or mucous membrane 4) Inhalation

Hypomanic Episode (3)

1) Less severe version of a manic episode 2) Similar criteria for manic episode, although the duration is a minimum of 4 days 3) Changes in behavior but no marked impairment in functioning or hospitalization

Genetic Aspects of Addiction: What might genes be affecting? (4)

1) Mechanisms of the drugs (how effective, how fast metabolized, neurotransmitter transporters, etc) 2) Inhibition-ability to override impulses 3) Risk taking (affecting sampling) 4) Factors taken into account in genetic studies: Genetic effect, Shared environmental effect, Unique environmental effect

Cluster A: Odd or Eccentric Personality Disorders (3)

1) Paranoid personality disorder 2) Schizoid Personality Disorder 3) Schizotypal Personality Disorder

Bipolar II (6)

1) Presence of one or more MDE 2) Presence of at least one Hypomanic Episode 3) There has never been a manic episode 4) Symptoms cause a change in functioning observable by others 5) 1 in 10 Bipolar II develop full manic or mixed episode 6) Differences may be due to diagnostic variation (e.g. requirement of MDE for bipolar II)

Depressants: Barbiturates

A barbiturate is a drug that acts as a central nervous system depressant, and can therefore produce a wide spectrum of effects, from mild sedation to death. - Bind to GABA-A barbiturate site - Non-specific inhibitory effect, overdose can cause death - Possible bad drug interaction (ie with alcohol) - Tolerance develops: Increase in liver enzymes, Adaptation of neurons, Results in physical and psychological dependence - Not as commonly used anymore

Acute Manic Episodes

A manic episode is a mood state characterized by period of at least one week where an elevated, expansive, or unusually irritable mood exists. A person experiencing a manic episode is usually engaged in significant goal-directed activity beyond their normal activities. Treatments?: - Lithium - Anti-epileptic medications (Gabapentin, Benzodiazepines & Others) - These drugs, albeit in lower doses, are the maintenance medications used to prevent relapse

Treatment of Mood Disorders: Transcranial Magnetic Stimulation

A noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve symptoms of depression. TMS is typically used when other depression treatments haven't been effective. Localized electromagnetic pulse - fewer side effects - no anesthesia - need many and frequent treatments - efficacy is likely good compared to medications but not as good as ECT - More studies needed

Lithium

A treatment to acute manic episodes - First used in the mid-19th century to treat "gouty mania" and "mental derangement" - Salt formulations of the element lithium - May work to decrease neuronal excitability via internal effects on the neurons - We know much more about the cellular signaling related to lithium - Primary treatment for bipolar disorders (50% respond (a significant reduction 50% in mania), May help in prevention of future episodes in over 60% of patients) - Narrow therapeutic window (Too little -ineffective; Too much - toxic, lethal)

Depressants: Benzodiazepines

A type of medication known as tranquilizers. Familiar names include Valium and Xanax. They are some of the most commonly prescribed medications in the United States. When people without prescriptions obtain and take these drugs for their sedating effects, use turns into abuse - Binds to GABA-A receptor - Potent anxiolytic, anticonvulsant, muscle relaxant - Less overdose risk than barbiturates, so now are more common

Drug Therapy for Depression

About 60-70% respond to treatment; no promise of relapse prevention some patients require long-term maintenance Side effects: - Common: sedation, dry mouth, nausea, tremor, dizziness, blurred vision, sweating, constipation, fatigue, sexual dysfunction, suicide (adolescents) - Rarer: cardiac arrhythmia, heart attack

Psychopharmacology of Alcohol

Alcohol is a general CNS depressant, NOT a stimulant - Initial effect is to deactivate inhibitory centers so commonly thought to be a stimulant - Expectancies determine hoe effects are experiences (Eg. if given alcohol or placebo, effects on aggression and sexual arousal depends more on pretreatment expectancy than on actual active substance)