Psychopharmacology Flashcards

Flashcards to help study for your psychopharmacology exam.

Ligand-gated ion channel partial agonist

If no agonist is present, then increases activity. If full agonist is present, then decreases activity.

Allosteric modulation

Some chemicals can bind to receptor sites that are separate from the primary neurotransmitter receptor site, but that can alter the main neurotransmitter receptor function.

Positive allosteric modulation

increases the functional outcome of the primary or ‘gatekeeper’ receptor.

Negative allosteric modulation

is where the functional outcome of the gatekeeper receptor is reduced. E.g., Prozac, a selective serotonin reuptake inhibitor (SSRI), affects the 5-HT reuptake receptor modulation site, reducing the 5-HT reuptake.

Co-transmission

A neuron can release multiple NTs. This is called co-transmission. This can work to affect the postsynaptic neuron by the two separate effects on postsynaptic neurotransmitters

Anxiety and Anxiolytics

Since the 1980’s, antidepressants have been used to treat anxiety

Pharmacodynamics

the study of the effect of drugs on the body (side effects)

Pharmacokinetics

the study of the effect of the body on the drug (how body breaks down the drug into an inactive substance and how long this takes)

Anxiolytics Used Historically

Alcohol (contains ethanol), Opium (contains morphine & codeine), Bromide salts (mechanism not clear)

Benzodiazepines Mechanisms of Action (MoA)

Inhibit neural activity via positive allosteric modulation of GABA(A) receptors

GABA(A) receptors

Ligand-gated chloride ion (CI-) channels that when they are activated they open a chloride ion channel, allowing CI- ions into the cell which hyperpolarises the membrane.

In relation to anxiety, what might generalised inhibition of neural communication result in?

reduction in general activity because it’s not getting the signals it is used to, i.e., cognitive functioning will be reduced.

Why don’t benzo’s affect CI- channels by themselves?

allosteric modulators are not activated if there is no receptor bound.

Pharmacodynamics of Benzos

Strongly increase GABA(A) mediated inhibition of neural communication

Main effects of Benzos

sedation, sleep induction, anticonvulsant actions, muscle relaxation and general reduction of signal transmission

Efficacy of Benzo as Anxiolytics

Reduce anxiety symptoms for the first 2 weeks, but there is no long term benefit

Key Side Effects of Benzos

Drowsiness, dizziness, lack of coordination and concentration, Decreased libido, erectile dysfunction, Depression, disinhibition, Hypotension

Why are the side effects exacerbated when combined with alcohol or some other drugs?

because we have an alcohol site which works similar to allosteric modulation site. It multiplies the effect because benzo already affects GABA and alcohol makes that effect even stronger.

Long Term Side Effects of Benzos

Cognitive impairment, increased anxiety and depression, anhedonia, altered perception of self and relationships (i.e., the opposite to what the drug was doing initially)

Tolerance

still taking the drug but has less of an affect

Withdrawal

stop taking the drug and don’t have enough neurotransmitters

Prescription of Benzos

Better results for the treatment of panic disorder, generalised anxiety disorder and social anxiety disorder

When should patients be prescribed Benzos?

Due to problems of tolerance and withdrawal, usually reserved for patients who have not responses to at least three previous treatments. NOT a first line treatment

When is the only time Benzos should be used as first-line treatment?

Only first-line treatment when short-duration treatment is sought (as less problems with tolerance/withdrawal) e.g., for a few days to deal with emotional trauma, particularly to help with sleep

Barbiturates

Very similar to benzo, used as anxiolytics prior to benzo but had worse side effects so they are rarely used today

Main mechanism of Barbiturates

positive allosteric modulation of GABA(A), with an additional antagonism of NMDA Na+ Channels

Why are Barbiturates rarely used today?

Seen as a huge breakthrough for anxiety, insomnia and seizures but extremely addictive and often fatal as it can slow down the heart too much (e.g., Marilyn Monroe)

Antidepressants Drug Recommendations History

1960’s - GAD: anxiolytics, Anxiety disorders: anxiolytics, MDD: antidepressants

1st Generation Antidepressants

Monoamine oxidases inhibitorys (MAOIs) – 1950s, Tricyclic Antidepressants (TCAs) – late 1950s

2nd Generation (novel) antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., fluoxetine (Prozac); 1988 first blockbuster, Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Monoamine Oxidase Inhibitors (MAOIs)

Can have serious interactions/reactions with certain foods and beverages, alcohol and other drugs

Mechanism of MOAIs

Blocking the enzyme to stop it breaking down NA

MAOI-A

Preferentially inhibits enzymes that break down NA, DA and 5-HT.

MAOI Reversibility - Older Version

Older version: The MAOI is irreversibly turned off, and can never function as a MAOI again.

MAOI Reversibility - Newer Version

Newer version: Reversible inhibitors of monoamine oxidase, as the drug wears off, MAOI function returns to normal which is less problematic for overdose and side-effects

MAOI Side Effects

Hypertensive crisis (excessive NA, particularly when foods containing tyramine are consumed as they can increase the release of NA), Serotonin syndrome (excessive 5-HT, particularly when other drugs that increase 5-HT levels are used (e.g., St John’s Wort, tryptophan, SSRIs), Dry mouth, nausea, diarrhoea or constipation, Headache, drowsiness, insomnia, Dizziness or light headedness

Discontinuation symptoms of MAOIs

Anxiety, Flu like symptoms, Agitation, Insomnia, Sweating, Nausea, and Malaise

Tricyclic Antidepressants (TCAs)

TCAs have generally been replaced by antidepressants that cause fewer side effects but in some cases relive depression when other treatments have failed

TCA Mechanisms

Have a range of pharmacodynamic actions primarily due to the reuptake of 5-HT and NA (no effect on DA)

TCA Side Effects

Blurred vision, constipation, dry mouth, drowsiness, hypotension, urine retention, excessive sweating, tremor, sexual dysfunction, weight loss, increased appetite à weight gain

SSRIs and SNRIs

First line of treatment for anxiety and depression, generally well tolerated (SSRIs more than SNRIs)

SSRIs and SNRIs Mechanism

They block reuptake, meaning there is more 5-HT and NA available for neural function

SSRI - Side Effects

Weight gain, insomnia, discontinuation symptoms after abrupt withdrawal, initial increased nervousness, nausea, sexual dysfunction.

SNRIs - Side Effects

Weight gain, disturbed sleep, discontinuation symptoms after abrupt withdrawal, high blood pressure

Antidepressant efficacy (all drugs)

Up to 1/3 of people achieve full remission, About 1/3 of people get some benefit, About 1/3 of people don’t get any benefit, Benefits reduce with duration of use, Benefit stops once treatment stops

DeRubeis et al., (2005)

Showed similar benefits of pharmacological ang cognitive therapy at 8 and 16 weeks, There was some indication of reduced benefit for pharmacological therapy between 16 weeks and 12 months of treatment, Once treatment had finished, psychotherapy had longer-lasting benefits than pharmacological treatment (over a 12-month period)

Antidepressants and suicidality

It has been reported that antidepressants increase suicide risk

Antidepressants and suicidality - FDA

The Food and Drug Administration (USA) requires a warning on all antidepressant medications that suicide ideation is a potential side effect

Monoamine Hypothesis of Depression

The hypothesis is that reduced MA levels in the brain cause depression

Monoamine Hypothesis of Depression - Evidence

Reserpine inhibits vesicular MA transporter, this reduces synaptic MA levels, therefore thought that the resultant depression was due to reduced MA levels. Additionally, antidepressant effect of drugs that enhance MAs (MAOI, TCA).

Difficulties with MA hypothesis - Mirtazapine

Isa 5-HT 2A, 5-HT 2C and adrenergic antagonist, thus reducing 5-HT and NA function, Is described as a noradrenergic and specific serotonin antidepressant (NaSSAs) and is extremely efficacious

Refinements to the MA hypothesis

Different receptor subtypes might be differentially related to depression

The Glutamatergic System

System based on the main excitatory neurotransmitter, glutamate (GLU)

The Glutamatergic System - GLU

GLU contributes to over half the brain’s synapses

The Glutamatergic System - GLU's Main Receptor

GLU’s main receptor is NMDA, which activates NA+ and CA + ion channels (causing depolarisation)

Another perspective is that serotonin may be important, but only as a mediating neurotransmitter system

the real antidepressant effects might occur via different NT systems, and SSRIs might help with depression because they affect these other systems, rather than because 5-HT affects depression itself

Ketamine

NMDA antagonism is psychotomimetic – it induces psychosis

Cognitive Enhancers

Designed to improve attention, memory, mental alertness, concentration, energy levels, wakefulness or treat disorders such as ADHD, dementia, schizophrenia, stoke, aging

How do Cognitive Enhancers work?

Enhances work in several different ways to act on multiple body systems, the key factor here is neurotransmitters

Enhancing attention

Dopamine and Norepinephrine Pathways mediating attention, verbal fluency, serial learning, sustaining and focusing attentions and impulse control, Additionally, reward mediated behaviour, movement, appetite, mood and memory

Enhancing Attention

Based on their functions Arousal/focus = increase dopamine/noradrenaline, Inattention = decreased dopamine/noradrenaline

ADHD Background

A disorder of attention, first appeared in the DSM-II (1968)

ADHD Criteria - Inattention

Children must show 6 or more, adults 5 or more, symptoms of inattention for at least 6 months

ADHD Criteria - Hyperactivity & Impulsivity

Children must show 6 or more, adults 5 or more, symptoms of hyperactivity and impulsivity for at least 6 months All symptoms are inappropriate for developmental age

ADHD Criteria

Several symptoms present before 12 years of age, and present in two or more settings Must interfere with social, school, or work functioning

ADHD Criteria

Symptoms are not better explained by another mental disorder

ADHD Subtypes

Primarily Inattentive: easily distractible or inattentive, but isn’t hyperactive or impulsive, Primarily Hyperactive-Impulsive: symptoms of impulsivity and hyperactivity, Combined: mixture of symptoms

Attention Pathways

Dopamine: projects from ventral tegmental area in the brainstem to mesocortical and dorsolateral prefrontal cortex, Noradrenaline: projects from the locus coeruleus in the brainstem to the prefrontal cortex

Pharmacological Treatment of ADHD Mechanisms of Action

Stimulants increase the avalibity of synaptic dopamine (short acting 4 hours or long acting 8 hours)

Pharmacological Treatment Issues - Side Effects

Reduced appetite, weight loss, gastrointestinal upset, sleeping problems, headaches, worsening of underlying affective and anxiety disorder

ADHD Efficacy

Robust effects for amphetamine-based medications compared to placebo in children and adolescents, Robust effects for methylphenidate-based medications compared to placebo in children and adolescents

Enhancing Memory - Acetylcholine

encoding of working and spatial memories by attenuating towards sensory features of stimuli; increases LTP; modulates hippocampal neurons. Other functions are on the parasympathetic nervous system

Dementia

Umbrella Term – heterogenous and progressive neurocognitive disorders:

DSM-5 Criteria – Dementia

Referred to as Major Neurocognitive Disorder (MNCD)

DSM-5 Criteria – Dementia

Significant decline from a previous level of performance: Complex attention – sustained, divided, selective, speed

Alzheimer’s Disease

Characterised by: Neurological symptoms: neurodegeneration in hippocampus, amygdala, hypothalamus, cortex

Hallmarks of Alzheimer’s Disease – Amyloid-Beta Plaques

protein implicated in enzymatic, antioxidant and anti-inflammatory pathways

Neurofibrillary (TAU) Tangles

Proteins that provide flexibility, stability to axons; nutrient transport

The Cholinergic Hypothesis of Alzheimer’s Disease

Dysfunction in the acetylcholine producing neurons contributes to cognitive decline

Pharmacological Treatment of Alzheimer’s Disease

Most current drug treatments – boost availability of acetylcholine

Pharmacological Treatment: Issues

Goal is to provide an effective way to improve memory or at least slow the rate of memory loss – do not offer a cure

Alternative Treatment – CBD

neuroprotective, regenerative, anti-inflammatory, antioxidant, antidepressant, anxiolytic, properties

Nociceptive Pain

Most cases of acute pain where a strong, noxious stimulus impacts skin or deep tissue. Sharp, aching, throbbing sensation

Nociceptive Pain Pathway

Sensory/discriminatory pathway: informs intensity, location of painful stimuli, Emotional/motivational pathway: informs emotional and motivation aspects

Neuropathic Pain

Damage to, or dysfunction of, nay part of the peripheral or central nervous system. Characterised by burning, stabbing, buzzing or electric shock like

Segmental central sensitisation

Experience of pain continues even after tissue damage resolved

Suprasegmental central sensitisation

Plastic changes in brain sites within the nociceptive pathway = sensitisation (e.g., thalamus, sensory cortex)

Fibromyalgia

A chronic, widespread pain syndrome of no known cause

Focus on cognitive factors:

One or more physical symptoms that are distressing or cause disruption in daily life

Psychiatric Comorbidity with Pain

Comorbid with depression: 30-60%

Pharmacological Treatment of Pain

Most common prescribed medications are antidepressants (TCA, SSRI, SNRI)

Anticonvulsants

A series of compounds originally introduced for treatment of epileptic seizures; but variety of MOA so multiple use Most common for pain include: Carbamazepine (Tegretol; anticonvulsant) or Gabapentin (Neurontin; antiepileptic; should be first medication trialled)

Anticonvulsants - MOA

Precise MOA uncertain but they reduce the ability of neurons to fire at high frequencies (enhanced GABA inhibition, stabilising effect on neuronal cell membranes, action via NMDA receptor sites)

Psychological Treatments for Neuropathic Pain

Therapy targets improvements in physical, emotional, social, occupational functioning rather than pain resolution

CBT for Pain

Application of a biopsychosocial approach that targets behavioural and cognitive responses to pain. Develops coping strategies intended to manage pain

Insomnia

A condition of unsatisfactory sleep, in terms of either sleep onset, sleep maintenance or early wakening. Thus, it impairs daytime well-being and functioning.

Narcolepsy

A chronic neurological disorder of excessive daytime sleepiness. A nervous system disorder thought to be caused by a decrease in hypocretin (orexin)

Neurobiology of Sleep and Wakefulness

Key neurotransmitters here are histamine, dopamine, noradrenaline, serotonin, acetylcholine

Regular Activating System (RAS)

Diffuse neural network, projecting from midbrain and pons to the cortex (via the thalamus and hypothalamus)

Sleep/Wake switch

There is another set of circuits in the hypothalamus that regulate sleep and wake (the sleep/wake switch)