D,B+A Flashcards
Why is there a limited range of antidepressants?
Limited understanding of the precise mechanisms associated with depression
Most development of therapeutic drugs is based on the “monoamine hypothesis” but it is complex in nature, heterogeneous and associated with other comorbid psychiatric disorders
Biological testing of an individual is difficult
Can be a difficult regulatory environment. E.g. difficult to get approval to study psychedelics
New drug discovery for depression is very reliant on animal models
No single behavioural test can ‘model’ depression
What 7 things are studied when a new antidepressant is tested?
- Cognition and Emotion,
- Behavioural Despair,
- Social models,
- Hopelessness,
- Anxiety-like symptoms,
- Locomotor activity,
- Anhedonia
What are the 7 effects of Salvia divinorum (kappa opioid receptor agonist)?
1) Uncontrollable hysterical laughter
2) Becoming objects
3) Overlapping realities
4) Loss of the body or identity
5) Entering a 2-dimensional world
6) Revisiting places from the past
7) Weird physical sensations, being pulled or twisted
What is the role of the kappa-opioid system in antidepression?
Activation of CREB (cAMP-responsive-element-binding protein) by stress, mediates the induction of dynorphin (a kappa agonist), which then contributes to anhedonia-like symptoms.
CREB is activated by D1 dopamine receptors leading to increased expression of dynorphin. Dynorphin feeds back onto opioid receptors located in the ventral tegmental area (VTA).
Stimulation of these receptors inhibits the VTA neurons, which leads to anhedonia-related symptoms. Therefore, antagonists of kappa receptors might block the consequences of CREB-induced increases in dynorphin activity, and exert antidepressant effects in some individuals.
How were receptor selective opioid antagonists developed?
The message-address concept: The ‘message’ component of a ligand defines the primary receptor recognition (e.g. to a receptor family) while the ‘address’ portion confers selectivity to a particular receptor subtype.
What are pharmacophores?
A pharmacophore is a set of structural and electronic features that are required for a compound to bind to a biological target. Pharmacophores are used in drug discovery to identify potential lead compounds.
What are the 3 aims of treatment for depression?
- Remission
- Relapse prevention
- Function restoration
What are the 2 NICE recommendations for treating depression?
- Match the level of care to the severity
- Match closely the patients preference
What are the 6 different types of therapy offered in NICE?
- psychodynamic psychotherapy
- Counselling
- Interpersonal psychotherapy
- Individual behavioural activation
- Individual CBT
- Group behavioural activation
What are the 4 more common antidepressant treatment escalations?
- SSRIs
- Alternative SSRI
- Recognised combo
- Addition of mood stabiliser/antipsychotic
What are the 3 less common antidepressant treatments?
- MAOIs
- Tricyclics
- Vortioxetine
What are the 3 ways that antidepressant therapy monitored?
Duration
Efficacy
Side-effects
What are the 6 serotonergic side effects?
Gastrointestinal (nausea, diarrhoea, changes in appetite)
Sexual dysfunction e.g. delayed ejaculation
Insomnia & agitation
More rarely bruising and bleeding (antiplatelet effect - beware those also on aspirin)
More rarely hyponatraemia
Withdrawal syndrome
What is serotonin syndrome?
A reaction when two or more agents increasing levels of serotonin are co-prescribed
Onset is usually rapid, often occurring within minutes to hours of elevated serotonin levels
Serotonin syndrome encompasses a wide range of clinical findings
Currently seen as more a spectrum, ‘serotonin toxicity’ as a continuum of serotonergic effects ranging from mild through to a life-threatening
What are the 6 cognitive effects of serotonin syndrome?
headache
agitation
hypomania
mental confusion
hallucinations
coma
What are the 5 autonomic effects of serotonin syndrome?
shivering
sweating
hyperthermia
vasoconstriction
tachycardia
What are the 3 somatic effects of serotonin syndrome?
myoclonus (muscle twitching)
hyperreflexia
tremor
What are the 5 ways of managing serotonin syndrome?
Stop interacting agents
Support organ function
Managing temperature
Agitation and muscle twitching use benzodiazepines
Serotonin antagonist cyproheptadine can be used
What 5 things do patients need to know before starting antidepressant therapy?
Symptoms may get worse in first week to 10 days, including increased anxiety & suicide ideation (SSRIs)
Once well treatment continued for at least 6 months to prevent relapse as depression often reoccurs
The chances of staying well are improved by antidepressants (prophylaxis)
Greater than 2 major depressive episodes consider long-term prophylaxis at full therapeutic dose, some people may need treatment for several years
Antidepressants are not addictive but can cause withdrawal so should not be stopped or changed suddenly: taper down
What do patients need to know about stopping antidepressants?
When stopping antidepressants, some patients experience uncomfortable and distressing withdrawal effects
Not all patients experience these symptoms, For others withdrawal symptoms can be mild and go away relatively quickly. Other people can have more severe symptoms which last much longer (sometimes months or more)
What is treatment resistant depression?
One third of people will not respond to their first antidepressant
About 20% of people never respond to antidepressants and may seek ECT or augmented combinations
Try switching to another agent, same class or different if adverse effects
Can augment with another medication e.g. lithium, sodium valproate or olanzapine
What is bipolar?
Bipolar disorder is a recurrent and often chronic mental illness marked by alternating periods of abnormal mood elevation and depression associated with a change or impairment in functioning.
The long-term course of illness is characterised by a predominance of depression, although a history of at least one manic, hypomanic, or mixed episode is required to make the diagnosis of a bipolar disorder.
Misdiagnosis of bipolar disorder is common, with unipolar major depressive disorder the most frequent diagnostic error made.
The management of acute mania requires mood stabilisers or atypical antipsychotics, as monotherapy or in combination. There are fewer approved treatment options for acute bipolar depression; traditional antidepressants are not indicated.
Bipolar disorder requires an individualised long-term management plan that includes maintenance medication(s), adjunctive psychosocial therapies, careful monitoring for any treatment-emergent complications, and promotion of a healthy lifestyle including sleep hygiene, exercise, and stress management.
How is bipolar treated pharmacologically?
Lithium
Anti-convulsant medications such as valproate or lamotrigine
Antipsychotics
Benzodiazepines
Antidepressants
How is lithium used therapeutically?
Offer lithium as a first‑line, long‑term pharmacological treatment for bipolar disorder
But taking lithium erratically is probably worse than not taking it at all
Ideally the decision to take lithium should be a joint one so the patient has the chance to consider the issues around side-effects and monitoring
Therefore acute treatment of either pole of the illness is likely to focus on other treatments, despite the fact that lithium can have acute efficacy in both depression and mania
Mainly used prophylactically:
Reduce both depressive and manic phases
Long term treatment to prevent relapse
Effects seen after 3-4 weeks of treatment
What is the therapeutic range of lithium?
Therapeutic range; 0.4 mmol/L – 1.0 mmol/L
Potentially fatal > 1.5mmol/L
How can lithium be used effectively?
Dose adjusted according to serum-lithium concentration and once daily administration is preferred when treatment is stabilised
There are several key drug interactions including ACEI, diuretics and NSAIDs (including OTC preparations)
Monitoring of adverse effects including renal and thyroid function are key
A single daily dose regimen is associated with less polyuria, a reduction in permanent renal damage and better compliance
Solid dose forms (lithium carbonate) and liquids (lithium citrate) need careful dose conversion if swapping between them
Preparations vary in bioavailability by brand, stick to the same whenever possible
Abrupt withdrawal is necessary in severe toxicity but if possible should otherwise be avoided – rebound mania can be severe and difficult to treat
How is lithium monitored?
Therapeutic serum-lithium concentrations should be taken 12hrs post-dose and the target range is usually 0.4–0.8 mmol/litre (may be as high as 1mmol/litre in specific cases)
Weekly monitoring is required while treatment is established or re-started
Monitoring of lithium levels and other key parameters including renal function should be undertake at least every 6-months for patients on a stable dose, more frequently (3-monthly) in higher risk groups
several variability factors for PK profile including age, body weight, renal function and pregnancy
The pharmacokinetic profile of lithium is linear within the dose regimen used in clinical practice
What are the 10 acute side effects of lithium?
- Polyuria and polydipsia (renal problems)
- Weight gain
- Aggravation of skin disorders
- Tremor, Muscle twitching, Dysarthria
- Nausea, Vomiting, Appetite loss, Diarrhoea
- Sluggishness, Languidness, Drowsiness
- Coma
- Hyper-reflexia, Fasiculations
- Choreiform and Parkinsonian motor symptoms
- Seizure and Convulsions
What are the 3 chronic side effects of lithium?
- Thyroid goitre
- Nephrotoxicity
- Hair loss
What is the MoA of lithium?
We don’t really know!
Monovalent cation that permeates voltage-gated sodium channels, not removed by Na/K ATPase
Depolarization of excitable cells
Inhibition of phosphatidyl inositol pathway
Prevents agonist stimulated IP3 formation
Inhibition of glycogen synthase kinase 3 (GSK3)
Involved in apoptosis and amyloid formation
What are the symptoms of lithium toxicity?
Gastro-intestinal disturbances (vomiting, diarrhoea),
Visual disturbances
Polyuria
Muscle weakness
Fine to coarse tremor
CNS disturbances (confusion and drowsiness increasing to lack of coordination, restlessness, stupor)
Abnormal reflexes, myoclonus
When is CBT recommended?
Depression, anxiety, OCD, panic, social anxiety, phobias, and adapting to long-term health conditions.
When is family intervention therapy recommended?
Recommended to help families work together to support a loved one who has a severe mental health disorder
When is behavioural activation therapy reccomended?
Subthreshold depressive symptoms, mild to moderate depression, and severe depression.
When is trauma focused CBT/EMDR recommended?
PTSD
When is DBT recommended?
Recommended for borderline personality disorder.
Initiating a conversation around deprescribing?
Initiated by the patient
- Respect the patient’s request – don’t be dismissive
- Exploring reasons for the request
Initiated by a healthcare professional
- Don’t rush a patient into a decision to stop/reduce
- Explain reasons
- Be prepared for queries about prescribing decisions made previously. Explain that our understanding of the balance of risks and benefits of a medicine can change over time.
Factors to consider when deprescribing
- Is the patient symptom-free, and if so, for how long?
- What is the severity of adverse-effects (EPS, TD, sedation, obesity, etc.)?
- What was the previous pattern of illness?
- Has dosage reduction been attempted before, and, if so, what was the outcome?
- Is the patient in a period of relative stability, or are stressful life events anticipated?
- What is the social cost of relapse? (implications for family/work)
- Is the patient/carer able to monitor symptoms, and, if so, will they seek help?
Withdrawal or discontinuation reactions
Approximately half of patients will experience withdrawal symptoms on reducing or stopping their antidepressant. Variation between patients.
There is some evidence that tapering slowly can reduce the chance of intolerable withdrawal symptoms.
Clinical experience suggests that most patients take between 3 months and 2 years to withdraw in a tolerable manner from long-term antidepressant treatment.
What are the 6 most common withdrawal symptoms?
- Paresthesia/numbness
- Shock-like sensations
- Rushing noises
- Palinopsia
- Confusion/decreased concentration/amnesia
- Hypersensitivity
NICE guidelines on withdrawal
Explain to people taking antidepressant medication that:
withdrawal symptoms can be mild, may appear within a few days of reducing or stopping antidepressant medication, and usually go away within 1 to 2 weeks
Withdrawal can sometimes be more difficult, with symptoms lasting longer
Withdrawal symptoms can sometimes be severe if the antidepressant medication is stopped suddenly.
Recognise that people may have concerns about stopping their antidepressant medication and may need support to withdraw successfully.
Support:
- details of online or written resources that may be helpful
- increased support from a clinician or therapist (for example, regular check-in phone calls, seeing them more frequently, providing advice about sleep hygiene).
When stopping a person’s antidepressant medication:
- take into account the pharmacokinetic profile (half-life)
- slowly reduce the dose to zero in a step-wise fashion
- consider using smaller reductions as the dose becomes lower and using liquid preparations if needed
- ensure the speed and duration of withdrawal is led by and agreed with the person taking the prescribed medication
- ensuring that any withdrawal symptoms have resolved or are tolerable before making the next dose reduction
- recognise that withdrawal may take weeks or months to complete successfully
Do not stop a medicine abruptly unless there are exceptional medical circumstances such as the occurrence of serious side effects
Practicalities of withdrawal
Inform patients of potential withdrawal symptoms, but don’t sensationalise
Be realistic about timescales
Discuss differences between relapse and withdrawal symptoms
Be prepared for the plan to be flexible and responsive to the patient
If symptoms become intolerable, either hold the current dose for longer or return to the last tolerated dose and then make the next reduction smaller
Some patients gain access to tapering strips but these are not widely available
Final reductions may need to be very small
What is the prevalence of depression?
Lifetime prevalence of unipolar depression 5% - ~1 in 38 adults in the UK at any one time
Globally, more than 300 million people of all ages suffer from depression
Suicide is the second leading cause of death in 15-29-year-olds.
Co-morbidity is common
2/3 of those with MDD will also meet criteria for anxiety disorder at some point
MDD twice as common in women than men
Differences emerge in adolescence
Episodic, recurrent can lead to suicide (0.04-0.08%)
How do you diagnose depression?
EITHER Depressed mood most of the day, nearly every day
OR Diminished interest/pleasure in everyday activities (anhedonia), nearly every day
PLUS 4 or more of the following
Significant weight loss/gain (>5% in a month) or change in appetite
Insomnia/ hypersomnia
Slowing down of thought and reduction of physical movement
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt
Diminished concentration, or indecisiveness, nearly every day
Recurrent thoughts of death or suicide
How do you assess depression?
Clinician administered assessment scales
Hamilton Depression Rating Scale (HAM-D or HDRS)
Montgomery-Asberg Depression Rating Scale (MADRS)
Self-rating assessment scales
Beck Depression Inventory (BDI)
Why?
Assess severity of symptoms
Evaluate response to treatment
Promote self-management strategies
What is major depressive disorder (MDD)?
Episodic
Symptoms tend to dissipate over time
Once depression occurs, future episodes likely
Average number of episodes is 4 (Judd, 1997)
Subclinical depression
Sadness plus 3 other symptoms for 10 days
Significant impairments in functioning even though full diagnostic criteria are not met
What is Persistent Depressive Disorder (Dysthymia)?
Chronic depression
Depressed mood for at least 2 years (not severe enough for a MD episode)
PLUS 2 other symptoms:
Poor appetite or overeating
Sleeping too much or too little
Psychomotor agitation or retardation
Loss of energy
Feelings of worthlessness
Difficulty concentrating or indecisiveness
Recurrent thoughts of death or suicide
What is the criteria for manic and hypomanic episodes?
Elevated, expansive, or irritable mood
PLUS 3 of the following (4 if mood is irritable):
Psychomotor agitation or increase in goal-directed behavior
Excessive talking or pressured speech
Flights of ideas; racing thoughts
Reduced need for sleep
Grandiosity or inflated self esteem
Easily distractible
Excessive involvement in pleasurable activities with negative consequences e.g. spending sprees
For manic episode:
Symptoms last for 1 week OR require hospitalization
Symptoms cause significant distress or functional impairment
For hypomanic episode:
Symptoms last at least 4 days
Clear changes in functioning but impairment is not marked
What are the 3 forms of bipolar?
Bipolar I
At least one episode or mania or mixed episode
Bipolar II
At least one major depressive episode with at least one episode of hypomania
Cyclothymic disorder (Cyclothymia)
Milder, chronic form of bipolar disorder
Lasts at least 2 years
Numerous periods with hypomanic and depressive symptoms
What is the prevalence of bipolar?
Prevalence rates for bipolar disorder lower than MDD
1% for Bipolar I
Average age of onset in 20s
No gender differences
Tends to be recurrent
Severe mental illness
A third unemployed a year after hospitalization
Suicide rates high
What are the subtypes of depressive disorders?
Seasonal (SAD)
Episodes happen regularly at a particular time of year
Rapid cycling (Bipolar I and II)
At least 4 episodes within past year
Postpartum onset
Within 4 weeks of giving birth
Catatonic features
Extreme physical immobility or excessive peculiar physical movement
Psychotic features
Delusions or hallucinations
Melancholic
Inability to experience pleasure (anhedonia)
Which medical conditions are associated with mood disorders?
- Pulmonary disease (COPD, asthma)
- Endocrine disorders (Hypo/hyperthyroidism, diabetes)
- Cancer
- Cardiovascular disease, especially MI
- CNS (migraine, infection, tumour, stroke, head injury, hypoxia)
- Neurological disorders (Alzheimer’s, Epilepsy, Parkinson’s, Huntington’s, Multiple Sclerosis)
- B12, folate deficiency
- Chronic pain, back problems
- Sleep apnea
What causes mood disorders?
Genetic factors - Heritability estimates
93% Bipolar Disorder
37% Major depression
Neurotransmitter dysfunction
Monoamines – 5HT, noradrenaline, dopamine
Neuroendocrine – disruption of the hypothalamic-pituitary-adrenal axis
Neurogenesis – Decreased rate of newborn neurones in the adult hippocampus
Neuroinflammation – any chronic inflammatory condition could produce cytokines/inflammatory markers that are able to cross blood-brain barrier and activate microglia
Glutamate – glutamate antagonists e.g. ketamine (NMDAR antagonist) antidepressant
Psychosocial/environmental factors
Stressful life events e.g. marriage breakdown, loss of job
Co-morbidity e.g. chronic pain, substance abuse
Medication e.g. corticosteroids, oral contraceptives, interferon
What are the neurotransmitters that cause mood disorders?
Neurotransmitters most implicated in mood disorders are the monoamines:
MDD
Low levels of 5-hydroxytryptamine and/or noradrenaline (and/or dopamine)
Mania
High levels of noradrenaline and dopamine, low levels of 5-hydroxytryptamine
Based largely on the ability of known antidepressant drugs to facilitate monoaminergic transmission = ‘the monoamine hypothesis of depression”
Reserpine – inhibits 5-HT and NA storage – lowers mood
Tryptophan depletion – lowers brain 5-HT synthesis – induces relapse in recovered patients
What is the monoamine theory of depression?
depression is a functional deficit of 5HT and/or noradrenaline in the brain
What is the psychological treatment for mood disorders?
Interpersonal psychotherapy (IPT)
Short term psychodynamic therapy
Focus on current relationships
Cognitive therapy
Monitor and identify automatic thoughts
Replace negative thoughts with more neutral or positive thoughts
Behavioral activation
Mindfulness based cognitive therapy (MBCT)
Strategies, including meditation, to prevent relapse
electroconvulsive therapy
Reserved for
Severe depression with high risk of suicide
Depression with psychotic features
Treatment non-responders
Induce brain seizure and momentary unconsciousness
Unilateral ECT
Side effects
Memory loss
What are monoamine oxidase inhibitors?
e.g. phenelzine, tranylcypromine, iproniazid
Irreversible inhibitors of monoamine oxidase
MAO is widely expressed
Within nerve terminals regulates intraneuronal concentration of NA/5HT
In the gut wall inactivates endogenous/ingested
amines
Enzyme exists in two forms MAOA and MAOB
MAOA – substrate preference = 5HT
MAOB – substrate preference = DA
What is the ‘cheese reaction’ with irreversible MAOIs?
Tyramine (diet) normally metabolised by MAO in the gut/ liver.
During non-selective MAOI:
Tyramine not metabolised but absorbed
Tyramine has sympathomimetic effects
Can result in acute hypertension, headache, angina, cardiac arrest, pulmonary oedema, intracranial haemorrhage.
What are the major side effects of MAOIs?
- Hypotension (sympathetic block)
- Atropine-like effects
- Hepatocellular jaundice
Reversible Inhibitors of MAOA (RIMA)
e.g. moclobemide
Reversible action allows MAOA inhibition to be partially overcome by high concentrations of substrate, e.g. tyramine
Unlikely to result in ‘cheese reaction’ if tyramine or sympathetic amines ingested
Tricyclic antidepressants (TCAs)
e.g. imipramine, amitriptyline, clomipramine
Block the uptake of amines by nerve terminals
5-HT=NA»_space; DA
Competitive with endogenous substrate
Relatively non-selective
Receptor blockade e.g. mAChRs, HA, 5-HT
Contributes to side effect profile
Major metabolites also active
What are the major side effects of TCAs?
- Sedation
- Atropine-like (muscarinic blockade)
- Postural hypotension
- Mania and convulsions (rare)
- Dysrhythmia and heart block
What happens when acute overdose of TCAs?
- Confusion, mania
- Cardiac arrhythmias
- Coma
- Respiratory depression, hypoxia
What are SSRIs?
e.g. fluoxetine (Prozac), paroxetine, citalopram
Developed by Eli Lilly in 1980s on the concept that
‘biological’ components of depressive illness are sensitive to antidepressant effects on NA systems
‘emotional’ components of depressive illness are sensitive to antidepressant effects on 5-HT systems
The most commonly prescribed class of antidepressants = 1st line
Also used to treat anxiety disorders
SSRIs vs TCAs
Better side-effect profile?
Safer in overdose
No evidence of greater efficacy
No evidence of more rapid onset
Monoamine receptor blockers
Mirtazapine – blocks a2 adrenoceptors/5HT2C receptors
Enhanced NA/5HT release
Trazodone - blocks 5HT2A/2C and 5HT reuptake
Mianserin – blocks multiple 5HT receptors, a1/2 adrenoceptors
Agomelatine – blocks melatonin receptors
Useful for depression associated with sleep disturbance
What are the 4 limitations of antidepressants?
Efficacy of antidepressants
< 40% achieve remission from symptoms
Robust effect in preventing relapse in recurrent MDD
Tolerability
side effect profile deters use e.g. emotional blunting/detachment with SSRIs
Time to onset/discontinuation effects
Typically 4-6 weeks to onset of therapeutic benefit
Safety of antidepressants
Risk of suicide
Older drugs are cardiotoxic, dangerous in overdose
Issues with the monoamine theory
Immediate short-term pharmacological effects
MAOIs increase 5-HT, NA by inhibiting metabolism
TCAs increase 5-HT, NA by blocking reuptake
SSRIs increase 5-HT by blocking reuptake
Clinical effects appear to take weeks to onset
Suggests chronic adaptive changes in response to antidepressants rather than acute
Medication for bipolar
Aka “mood stabilizing drugs”
Lithium
Up to 80% receive at least some relief with this mood stabilizer
Potentially serious side effect = Lithium toxicity
Anticonvulsants (prevent relapse to depression?)
e.g. valproate, lamotrigine
Antipsychotics (co-prescribed, where mania predominates?)
e.g. olanzapine, risperidone, quetiapine, aripiprazole
What is anxiety?
Anxiety is a normal, physiological response to threatening situations that serves a protective function
Anxiety is pathological when there is a bias to interpret non-threatening situations as threatening
The concern about the stressor is out of proportion to the realistic threat and can occur without exposure to an external stressor = pathological anxiety
Negative cognition:
Bias to interpret unthreatening situations as threatening
Context/memory/reinforcement
Physiological symptoms: autonomic activation
Racing heart
Palpitations
Restlessness
Sweating
Increased blood pressure
What are the 7 types of anxiety disorders?
- Simple/Specific phobias
- Social phobia/ Social anxiety disorder (SAD)
- Panic disorder (PD)
- Posttraumatic stress disorder (PTSD)
- Generalized anxiety disorder (GAD)
- Obsessive compulsive disorder (OCD)
- (Premenstrual dysphoric disorder (PMDD))
How do you make a diagnosis of GAD?
DSM criteria for generalized anxiety disorder include:
- Excessive anxiety and worry about several events or activities most days of the week for at least six months
- Difficulty controlling feelings of worry
At least three of the following symptoms in adults
- restlessness
- fatigue
- trouble concentrating
- irritability
- muscle tension
- sleep problems
What are the causes of anxiety disorders?
Largely unknown
Abnormal regulation of brain areas involved in stress/fear
Several neurotransmitter systems implicated:
- Underactivity of 5HT system?
- Overactivity of NA system?
- Disruption in level of GABA inhibition?
reduced expression of GABAA-receptors
reduced function/regulation of GABAA-receptors by benzodiazepines
reduced function/regulation of GABAA-receptors by neurosteroids
Genetic and environmental factors play a role
What is the treatment of anxiety disorders?
Pharmacotherapy
- b-blockers – target autonomic symptoms
- Benzodiazepines
- Antidepressants (SSRIs)
- Buspirone (partial agonist at 5-HT1A receptors)
Evidence-based psychological interventions
- Low intensity interventions e.g. self-help approaches
- High intensity interventions e.g. CBT for social anxiety disorder
- Stepped-care approach
What are beta blockers for anxiety?
Treat the physiological symptoms of anxiety
Reduce the sympathetic manifestations of stress/fear response
No effect on affective components
Useful in treating phobias
Evidence for use in curing phobias
Useful in treating PTSD
Effects on memory consolidation
Benzodiazepines bind to an allosteric site on the GABAA receptor
Functional GABAA receptors are pentameric combinations of different subunits arranged to form the integral chloride ion channel
Most prevalent receptor in mammalian brain consists of two α, two β and one γ-subunit
GABA binds between α and β-subunits – so 2 molecules to activate receptor
Benzodiazepines bind at the interface between α/γ-subunits and affect chloride ion conductance to regulate GABAergic inhibition
Development of benzodiazepines (BZs)
Developed in the 1950’s for their tranquilizing properties
First trials in monkeys noted “loss of fear, hostility, and aggressiveness; increased friendliness; still fully in touch with environment”
In the early 1970s more potent BZs such as chlordiazepoxide (Librium) and diazepam (Valium) accounted for 50% of all US psychoactive drug prescriptions
Fast acting and effective relief of anxiety and safer than barbiturates e.g. pentobarbital
Structure of benzodiazepines
The core of all BZ ligands is a benzene ring joined to a 7-membered 1,4-diazepine ring
R side groups influence the
AFFINITY of the BZ to bind the receptor
INTRINSIC EFFICACY of BZ to produce a functional effect
BZ AGONISTS have 100% intrinsic efficacy
BZ INVERSE AGONISTS bind to the site but produce the opposite effect and are said to have negative intrinsic efficacy.
BZ ANTAGONISTS bind to the BZ site but are unable to activate the receptor (intrinsic efficacy = 0)
other properties such as lipophilicity, water solubility etc.
What are the 5 downsides of benzos?
- Memory loss
- Sedation
- Abuse potential (?)
- Addictive (?)
- Withdrawal syndrome
What is sleep are what are it’s 4 purposes?
A readily reversible state of reduced responsiveness to, and interaction with, the environment
What is it for?
- Cortical recovery
- Organizing/storing memories
- Metabolism/weight homeostasis
- Sleep deprivation may provide clues
What is REM sleep?
EEG like that of an active waking brain (“paradoxical sleep”)
Oxygen consumption of brain is high
Vivid dreaming
Loss of skeletal muscle tone (atonia)
Bursts of rapid eye movements
Sympathetic activity predominates
What is non-REM sleep?
Non-REM sleep is a rest period
Muscle tension reduced
Body temperature lowered
Energy consumption lowered
Increase in parasympathetic activity
Brain rhythms slow (“slow wave sleep”)
What are the brain mechanisms of sleep?
Ascending reticular activating system (RAS)
Locus coeruleus – noradenaline
Raphe nuclei – serotonin
Brainstem/forebrain – acetylcholine
Midbrain – histamine
Firing of these neurons = awakening
Firing of these neurons = falling asleep
What are the 4 sleep regulating substances?
Interleukins
immune mediators
Melatonin
derived from 5-HT in endocrine pineal gland
cure for jet lag?
Hypocretin-orexin
Hypothalamic neuropeptide regulates appetite, metabolism
Stimulants
e.g. caffeine, cocaine, amphetamine
What are the 4 types of insomnia?
Transient insomnia
e.g. noise, shift work, jet lag
Short-term insomnia (“primary insomnia”)
e.g. emotional problems, stress, anxiety
Chronic insomnia (“secondary insomnia”)
e.g. pain, depression, anxiety, alcohol abuse, dyspnoea
Fatal familial insomnia – very rare
6 self-help tips for better sleep?
- regular sleep hours
- restful environment
- move more
- be awake if awake
- write worries
- less caffeine
What are hypnotics?
Good sleep hygiene = behavioural, environmental & temporal factors?
Hypnotic = a drug used to induce and maintain sleep
Use should be
- intermittent
- short term (< 2 weeks) if daytime impairment is severe
(tolerance/withdrawal syndromes can occur)
Treatment aims to shorten time to sleep, increase total duration of sleep, without suppressing sleep cycle and REM sleep
What are benzodiazepine hypnotics?
Long acting e.g. flurazepam/ Dalmane (2-keto)
May give rise to “hangover” effect
Short acting e.g. temazepam/ Restoril (3-OH), triazolam/ Halcion
little or no “hangover” effect
Rohypnol (flunitrazepam) – “date rape”
Little to distinguish between BZs in terms of efficacy, adverse effects or risk of dependency
Next-day residual effects common with diazepam, nitrazepam and flurazepam
What are the non-benzodiazepine hypnotics
Zaleplon, zolpidem, zopiclone (“Z drugs”)
Non-benzodiazepines that bind to GABAA receptor
Short duration of action
Less likely to cause rebound insomnia than BZs
Dependence may be a problem
What are the 2 types of OTC sleep aids?
Antihistamines
- Promethazine (Phenergan)
- Diphenhydramine (Nytol)
‘Natural remedies’
- Melatonin (Circadin)
- Chamomile tea/Lavender/Evening primrose oil/Valerian
