depression and anxiety case Flashcards
1
Q
what are the risk factors associated depression
A
- Gender ~ females: higher during reproductive yrs then trend reverses
- Age ~ predicted changes in recent decades – younger onset shorter duration, less frequent in elderly but some increases now coming through.
- Marital status ~ highest in separated, then widowers then divorced females.
- Socio-economic factors ~ social class 3 higher incidence than 1,2. Higher in rented accommodation, highest in street (roofless) homeless
- Ethnicity ~ Females: highest in Asian / South East Asian, then Whites lowest amongst West Indian / African.
- Males: No differences.
2
Q
what are the 3 classifications
A
Sub-threshold: Fewer than 5 symptoms
Mild: Few, if any, symptoms in excess of the 5 required to make the diagnosis and symptoms result in only minor functional impairment.
Moderate: Symptoms or functional impairment are between ‘mild’ and ‘severe’
Severe: Most symptoms and the symptoms markedly interfere with functioning. Can occur with or without psychotic symptoms.
Symptoms must be present for two weeks.
3
Q
what are the key 3 symptoms for depression?
A
- LOWERED MOOD (also referred to as ‘affect’)
- ANERGIA (Think: what does the prefix ‘a’ or ‘an-’ denote?) lack of energy
- ANHEDONIA (think opposites! What is a hedonist?)- no longer take pleasure of what they used to do
4
Q
what are the other symptoms associated with depression?
A
- Weight changes (can go up as well as down)
- Changes in sleep pattern ~ examples? Insomnia, sleeping in excess, disrupted sleep. Lowest level of cortisol leads to more depression. People with asthma will have IV hydro cortisol.
- Agitation / anxiety / somatisation
- Psychomotor retardation
- Psychotic features ~ delusions / hallucinations: note: these will be mood congruent
- Sexual dysfunction (essential to take a sexual history prior to any proposed pharmacological intervention ~ why??) many of antidepressants can induce sexual dysfunctions if they already have existing problems
- Decrease in self-esteem, self-confidence
- Feelings of guilt (often either over-valued /exaggerated or overtly delusional), worthlessness
- Self - harm / suicidal ideation / suicide (number of suicides in England + Wales each year?) 6000
5
Q
what are some of the causes of depression?
A
• Physical ~ numerous – exacerbates / causation; consider metabolic and other organic causes (everything from chronic pain to poorly-controlled thyroid dysfunction)
• Iatrogenic ~ ‘Now then, who’s prescribed depression this morning?’
The rest can be summed up by the following three words:
Loss and Regret*
…….Of job, status, relationship, health et cetera
‘Have you ever ignored a bill for a week? Yes? Well, ignore them for a year – I’ll save you a bed in St Pats’ (homeless hostel.) The vast majority of us are 6 failed mortgage re-payments away from homelessness.
* ‘I’d trade all my tomorrows for a single yesterday.’
6
Q
what are the 4 steps that the NICE guidelines say about depression?
A
Step One: All known and suspected presentations of depression
Step Two: Treatment of persistent sub-threshold depressive symptoms, mild to moderate depression.
Step Three: Persistent sub-threshold or mild to moderate depression that has failed to respond to initial interventions, moderate or severe depression.
ADs should be offered routinely to all patients, before psychological interventions
Step Four: Severe and complex depression; risk to life; severe self-neglect.
7
Q
what is step 1 from the NICE guidelines of treating depression?
A
Step One: All known and suspected presentations of depression
Who to assess? Those designated ‘High risk:’
• People with a past history of depression (relapse: 50-85%)
• Significant physical illness causing disability (DM, CHD
MS et cetera)
• Other mental health problems ~ e.g. dementia
Screening questions:
“During the last month have you often been bothered by feeling down, depressed or hopeless?”
“During the last month have you often been bothered by having little interest or pleasure in doing things?”
( these questions therefore explore / assess key symptoms, duration et cetera)
8
Q
what is step 2 from what the NICE guidelines say about treating depression?
A
Step Two: Treatment of persistent sub-threshold depressive symptoms, mild to moderate depression.
Watchful waiting: (NB this is applicable to mild depression only)
If the patient does not want treatment or may recover without further intervention, re-assess in two weeks time.
• Sleep and anxiety management.
• Exercise:
Advise pts of all ages that structured exercise of 45-60mins duration, three times a week for at least 10 -12 weeks has proven benefits in mild depression.
NICE ~ Treatment of Depression
• Guided self-help
• Computerised Cognitive Behavioural Therapy (CBT)
A useful website: www.rcpsych.ac.uk
Other psychological interventions – menu includes:
• CBT
• Cognitive Analytical Therapy
• Interpersonal therapy
• Psychodynamic (psychoanalytic) psychotherapy
9
Q
what does NICE guidelines say about antidepressants?
A
Antidepressants (ADs):
• ADs are NOT recommended for the initial treatment of mild depression because the risk : benefit ratio is poor.
(Adverse effects? Yes. Efficacy? Only Possibly)
• When mild depression persists after other interventions (see before) or is associated with psychological or medical problems consider use of an AD
• If a patient with a history of moderate or severe depression presents with mild depression consider (early) use of an AD. (If it remains appropriate – age? Co-morbidities? - then consider re-prescribing, at the treatment dose, the previously effective AD)
10
Q
what does step 3 say in the NICE guidelines about the treatment for depression
A
Step Three: Persistent sub-threshold or mild to moderate depression that has failed to respond to initial interventions, moderate or severe depression.
ADs should be offered routinely to all patients, before psychological interventions
KEY Medication counselling points:
• ‘Addiction’
• Potential side–effects
• Discontinuation symptoms
• Delay in full benefit, length of treatment.
Make available appropriate written information (+?)
Consider referral and collaborative care
11
Q
what is the monitoring risk for people who have depression?
A
Monitoring Risk:
• Pts at increased risk of suicide or younger than 30 years; follow up after 1 week.
If high risk of suicide: prescribe a limited number of ADs, consider additional primary support and telephone contact.
• Monitor for (increased) signs of anxiety, agitation and akathisia. If marked or prolonged review use of AD. Consider inter-class ‘switch’ or co-prescription of short-course, low-dose BDZ with frequent review.
12
Q
what are the drug treatment options for depression?
A
When a pt fails to respond to the initial AD (SSRI) prescribed then:
Ensure the AD has been taken as prescribed ~ correct dose, frequency, duration etc
• If response at the standard dose is inadequate and side-effects are tolerable consider an increase in dose in line with the SPC.
• If no response after 1 month then consider a switch in AD. If there has been a partial response then postpone decision to switch for 6 weeks.
If an AD is ineffective and / or poorly tolerated and if the decision is made
13
Q
what are the drug choices for 2nd line antidepressants?
A
Choices for a second-line antidepressant include: • Another SSRI • SNRI – Venlafaxine, duloxetine • Mirtazapine (NaSSA) • Moclobemide (RIMA) • TCAs ~ avoiding dosulepin
14
Q
what should be reviewed for people who have severe depression?
A
Continuing treatment:
Review pts who are not in the high risk grp after 2 weeks then every 2-4 weeks thereafter for first 3/12.
For pts with a moderate or severe depressive episode continue ADs for 6/12 after remission has been attained.
After 6/12 from remission, review need for continued treatment based on: number of previous episodes, age, residual symptoms and concurrent psychosocial difficulties.
15
Q
what other antidepressants choices are available?
A
Choice of Antidepressants:
• An SSRI (examples?) should be prescribed as first choice. As effective as TCAs (examples?) and less likely to be discontinued because of side effects/ toxicity (See later)
• If agitation / anxiety / akathisia occurs + persists either change AD or prescribe a benzodiazepine short-term and r/v in 2 wks.
• St John’s wort* ~ not recommended by NICE; there is a lack of evidence of efficacy in moderate / severe MDD. SJW is known to have numerous, clinically significant pharmacokinetic and pharmacodynamic drug-drug interactions.
16
Q
what does the NICE guidelines say about st john worts?
A
Although there is evidence that St John’s wort may be of benefit in mild or moderate depression, practitioners should:
• not prescribe or advise its use by people with depression because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)
• advise people with depression of the different potencies of the preparations available and of the potential serious interactions of St John’s wort with other drugs.
17
Q
what should a healthcare professional do/advise if a patient decides to stop antidepressants?
A
Stopping Antidepressants:
• Inform pts about the possibility of discontinuation symptoms on stopping / reducing or missing doses.
• Advise pts to take meds as prescribed.
• Reduce ADs gradually over a 4 week period.
• If pts experience mild withdrawal symptoms then reassure, if severe then re-introduce and decrement even more gradually.
18
Q
what does step 4 say in the NICE guidelines say for the treatment of depression?
A
Step Four: Severe and complex depression; risk to life; severe self-neglect.
Key Points:
• Assess symptoms, suicide risk, treatment history, psychosocial stressors, personality factors and any significant relationship difficulties.
• Re-introduce previous treatments that were inadequately delivered or adhered to.
• Consider ECT, multi-professional and in-patient care
• Crisis resolution teams (CRTs) should be used for pts with severe depression and presenting with significant risk.
19
Q
what is meant by treatment refractory depression?
A
This diagnosis is made when patients do not respond to two antidepressants, given sequentially.
70% will respond to the initial AD, of the remaining 30% half of these patients (50%) will respond to the second AD. This leaves a treatment refractory sub-population of 15%.
20
Q
what are the treatment options for Treatment Refractory Depression
A
Add Lithium (aim for plasma level of 0.4-1.0mmol/L)
(NICE recommended)
ECT (well established, effective. Poor public reputation)
Venlafaxine at doses >200mg/day (NICE recommended, STARD supported)
Add Tri-iodothyronine; 20-50micrograms/day (well tolerated, TFT essential supported by STARD)
SSRI + Bupropion{up to 400mg/day} ( supported by STARD)
SSRI + Buspirone {up to 60mg/day} (supported by STARD, poorly tolerated)
SSRI or Venlafaxine + Mianserin or Mirtazapine (NICE recommended, risk of serotonin syndrome, mianserin-induced blood dyscrasia)
21
Q
how do AD work
A
Concisely; ADs work by increasing the amount of certain chemicals that can influence the working of the CNS. This is the monoamine theory of depression ~ so-called because the chemicals involved are monoamine neurotransmitters, namely Serotonin and Noradrenaline
Early anti-hypertensives depleted / decreased levels of these NTs and people uniformly became depressed.
Anti TB drugs boosted these NTs and people who were depressed ‘got happy’
22
Q
what are the side effects of antidepressants?
A
SSRI: Nausea, vomiting, insomnia, anxiety/agitation/akathisia, sexual dysfunction, headache, rarely sedation
TCA: Sedation, dry mouth, blurred vision, constipation, sedation, urinary retention, cardiac irregularities (arrhythmias) and rarely increase in blood sugar, seizures
( See later)
23
Q
what are the symptoms of AD discontinuation syndrome
A
– “flu” like symptoms – gastrointestinal – anxiety – sleep disturbance – panic attacks
24
Q
what is the management if decide to discontinue AD?
A
- Gradually reduce antidepressant therapy.
- Reassure patient that symptoms will not persist.
- Reassure patient that symptoms are not indicative of a relapse.
25
what is meant by anxiety?
Anxiety disorders are neither minor nor trivial. These cause considerable distress, are disabling and often chronic in nature.
26
what are the different subtypes of anxiety?
```
• Specific phobia
• Social anxiety disorder
• Generalised Anxiety Disorder (GAD)
• Panic Disorder
• Agoraphobia
• Separation anxiety disorder
• Selective mutism
Please note that both Obsessive Compulsive Disorder (OCD) and Post Traumatic Stress Disorder (PTSD) are now considered diagnoses distinct from the anxieties clusters
```
27
what is meant by specific phobia?
marked fear or anxiety about a specific object or situation. (Duration; 6/12 +)
Social anxiety disorder
Persistent fear or anxiety about 1 or more social or performance situations that is disproportionate (6/12+)
GAD
Excess worry about a number of events or activities and difficulty controlling this (6/12+)
28
what is meant by seperation anxiety
Excessive fear or anxiety focussed on separation from home or attachment figures (1/12 in children, 6/12 in adults)
Selective mutism
Consistent failure to speak in social situations when there is an expectation to do so (1/12+)
29
what is meant by panic disorder?
Recurrent unforeseen panic attacks ~ i.e. an abrupt surge of intense fear (An initial panic attack followed by 1/12 of persistent worry about additional attacks)
• Repeated unpredictable attacks of severe anxiety occurring without warning unrelated to a specific situation
• Can peak within 10 minutes with many somatic / physical symptoms
• Can be combined with GAD or phobic disorders
30
what is meant by Agoraphobia
Marked fear or anxiety about situations where escape might be difficult (6/12 +)
This anxiety typically leads to a pervasive avoidance of a variety of situations ~ examples include: being alone outside the home or being home alone, being in a crowd of people, travelling by car, bus or plane or being on a bridge or in a lift.
31
what is the stepped-care model:
Step 1: Focus of intervention; all known + suspected presentations of GAD.
Nature of intervention; identification + assessment; education about GAD and treatment options; active monitoring.
Step 2: Diagnosed GAD that has not improved after education and active monitoring in 1 0 care.
Low intensity psychological interventions; Individual non-facilitated self-help, individual guided self-help and psycho-educational groups.
Step 3: GAD with an inadequate response to step 2 interventions or marked functional impairment.
Choice of a high-intensity psychological intervention (CBT / applied relaxation) or a DRUG TREATMENT
Step 4: Complex treatment-refractory GAD and very marked functional impairment ~ e.g. self neglect or high risk of self-harm.
Highly specialist treatment~ complex drug treatment and / or psychological treatment regimens; MDHT input, crisis services, day hospitals or in-patient care.
32
what are the risk factors associated with anxiety?
* Family History
* Childhood adversity
* Stressful life events
* Specific personality traits – excessive worrying
* Certain Parenting styles* ~ such as being over-protective, lacking emotional warmth or parents ‘modelling’ fear and avoidance
* Younger age
* Being female, unmarried or unemployed
* Poor physical or mental health
33
what is meant by generalised anxiety disorder?
* A persistent, excessive anxiety, apprehension or worry present for at least 6 months
* Chronic condition with acute episodes ~ peaks and higher peaks
* Often begins in early adulthood
* Twice as common in women than men
34
what is phobic disorder
* Phobia is an irrational fear out of all proportion to the situation or object
* Recognised as excessive but cannot be reasoned away.
* Sub-divided into agoraphobia, social phobia and simple specific phobia
35
what are some of the most common type of phobias?
1) Arachnophobia-spiders
2) Ophidiophobia-snakes
3) Acrophobia- heights
4) Agoraphobia (see previous)-
5) Cynophobia-dogs
6) Astraphobia-thunder and lightening
7) Trypanophobia-needle
8) Social phobias
9) Pteromerhanophobia- flying
10) Mysophobia- germs
36
what is meant by obsessive compulsive disorder?
* A time consuming obsession and compulsion which interferes with a persons day to day functioning, work or relationship
* If compulsion is resisted anxiety levels are increased
* Life time prevalence of 2%
* Males and females equally affected
37
what is meant by post traumatic stress disorder?
* Intense and prolonged can be delayed response to a particular trauma
* Characterised by emotional numbness, detachment, flashbacks, recurring memories and vivid dreams.
* Do not have to be personally involved can be a bystander or rescue worker
38
what is meant by Mixed disorders
• Both anxiety and depression present
It is essential therefore to consider the differing signs and symptoms presenting.
Global assessment scales should be used to provide objective measures to confirm diagnosis, assess / assign severity and monitor response to treatment interventions.
A variety of interventions both pharmacological and psychological may need to be initiated, optimised and monitored on an on-going basis.
39
what is the mechanism of anxiety?
2 brain systems involved in fear and anxiety:
• Defence system- responds to both learned and unlearned threats; can initiate fear, flight, fight or freeze behaviour
• Behavioural inhibition system- Responsible for avoidance behaviour - a neurobehavioral system thought to regulate negative affect and avoidance behaviour in response to threats or punishment. Individuals vary in the sensitivity of the system (refer to work by Kagan et al from 1984.)
40
what is the general management of anxiety disorder
* Shared decision making between the patient and individual promotes concordance and optimises outcomes
* Appropriate and usable information should be given to patients, carers, family members etc; medication information must be included
* Pts families etc should be informed of all appropriate self-help, support groups etc.
41
what is the treatment options
Discuss in a full and frank manner with the patient and his/her family / carers etc and give the following menu:
• Self-help
• Psychological therapy
• Pharmacological therapy
42
what is the pharmacological treatment for anxiety
If a person with GAD chooses drug treatment, offer a selective serotonin reuptake inhibitor (SSRI).
Consider offering sertraline first because it is the most cost-effective drug, but note that at the time of publication (January 2011) sertraline did not have UK marketing authorisation for this indication*. Informed consent should be obtained and documented. Monitor the person carefully for adverse reactions.
Do not offer a benzodiazepine for the treatment of GAD in primary or secondary care except as a short-term measure during crises. Follow the advice in the ‘British national formulary’ on the use of a benzodiazepine in this context (see following slide)
Do not offer an antipsychotic for the treatment of GAD in primary care.
43
Sertraline therapeutic indication
* Major depressive episodes. Prevention of recurrence of major depressive episodes.
* Panic disorder, with or without agoraphobia.
* Obsessive compulsive disorder (OCD) in adults and paediatric patients aged 6-17 years.
* Social anxiety disorder.
* Post traumatic stress disorder (PTSD).
44
what are the pharmacological treatments options
* Benzodiazepines
* Anti-depressants
* Anxiolytics – Buspirone
* Pregabalin
* Antipsychotics
* Beta-blockers
* Antihistamines
45
What is the MoA for Benzodiazepines
* Act on postsynaptic GABA-A receptors
* Responsible prescribing with appropriate monitoring ensures maximal benefit from BDZs as therapeutic agents.
* BDZs have been proven to be efficacious in certain situations for selected patients.
* Examples of this would include use as immediately acting agents for severe symptom control while awaiting other treatment to work and to ensure other treatments can be accessed ~ eg: CBT, IPT, ‘flooding’ / exposure etc
46
what is the benzodiazepine indications?
Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or causing the patient unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness.
The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate.
Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or causing the patient extreme distress.
47
MoA Selective Serotonin Reuptake Inhibitors (SSRIs)
* Inhibits reuptake of serotonin at post synaptic receptor site
* Increase central serotonergic activity
* ‘Onset of action may not appear for 6 weeks and the full response may take 12 weeks’ ~ discuss.
48
how does serotonin play a key role in the mode of action of SSRIs, SNRIs and certain TCAs
Serotonin (5-HT) plays a key role in the mode of action of SSRIs, SNRIs and certain TCAs.
5-HT facilitates defensive responses to potential threat (e.g. inhibitory avoidance) related to presentation of anxiety.
This action would be exerted at the forebrain – chiefly the amygdala and medial prefrontal cortex.
Chronic administration of antidepressants suppress panic attacks by increasing the release of 5-HT and enhances the response of 5-HT1A and 5-HT2A receptors in the midbrain (DPAG). The efficacy against generalised anxiety is thought to be due to desensitisation of 5-HT2C & to a lesser extent increased stimulation of 5-HT1A in the forebrain which results in less activation of the amygdala, medial PFC and insula by ‘warning signals.’
(This has been shown using functional neuroimaging in healthy volunteers and pts with anxiety disorders)
49
other treatments for anxiety
* Beta-Blockers – only treat somatic or physical symptoms (consider tolerability versus efficacy, relative and absolute contra-indications) eg propranolol
* Buspirone – complex mode of action (partial 5HT 1A agonist, acts on both Noradrenergic and Dopaminergic pathways) takes time to work (1/12 minimum) better than placebo, worse than BDZ in terms of efficacy and tolerability (drug interactions with cyp 450 3A4 inducers + inhibitors)
* Sedating Antihistamines ~ e.g. high dose Hydroxyzine (not recommended, following Cochrane systematic review of 2010)
50
MoA of Pregabalin
Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system, this causes conformational changes thereby reducing excitatory neurotransmission.
Relatively rapid onset of action, excreted unchanged (P’kinetic drug interactions therefore minimal)
Reduce dose in patients with renal impairment
Use when SSRI / SNRIs not tolerated – could consider as adjunct.
Monitor for misuse (10% of patients prescribed versus neuropathic pain report euphoria; rescheduled to CD3 from April 1st 2019)
51
what other treatment
• Antipsychotics – specifically used in PTSD and, occasionally in OCD ~ examples include SGAs such as Olanzapine, Risperidone and Quetiapine. NOT for routine use in GAD
• Other treatment options used in Social Anxiety Disorder and PTSD include valproate and carbamazepine.
Evidence base for the above is weak and in all cases the pharmacological treatment options should form part of the overall care package that also incorporates psychological interventions.
52
what is meant by schizophrenia?
Schizophrenia is a syndrome characterised by a broad range of cognitive, emotional and behavioural problems
53
what is the 'first rank' symptoms
1. Auditory Hallucinations:
• Voices repeating the subjects own thoughts
• Two or more hallucinatory voices discussing the subject / arguing in the third person
• Voices giving a running commentary on the subjects thoughts or behaviours.
Hallucinations; perceived in the absence of stimuli.
2. Thought insertion or withdrawal
3. Thought broadcast
4. Feelings, impulses or acts being experienced or carried out under external control ~ the patient feels therefore that he has become hypnotised or a robot
5. Being a passive & reluctant recipient of bodily sensations imposed by some external agency
6. Delusional perception.
Delusions: fixed (certainty) false (impossible, untrue, bizarre) beliefs that no amount of proof to the contrary will alter (incorrigibility)
54
what are the positive and negative clinical aspects of Schizophrenia
Positive symptoms:
• Hallucinations, delusions.
• Disorganised speech / formal thought disorder.
• Disordered / catatonic behaviour.
```
Negative symptoms:
These relate to the loss of normal functions;
• Flattening or blunting of affect
• Alogia (reduced production of speech)
• Emotional apathy
• Social withdrawal
• Lack of motivation
• Loss of pleasure (anhedonia)
```
55
what is the diagnosis summary for Schizophrenia
• Positive symptoms ~ hallucinations, delusions, thought disorders
• Negative symptoms ~ reduced self-care, motivation, anhedonia, alogia, affective blunting
• Reduced social functioning
There should be an absence of mood disorder ~ mania / depression
56
what are the clinical aspects of Schizophrenia
Aetiology of Schizophrenia:
Clinically, schizophrenia is heterogeneous so the aetiology is likely to be heterogeneous.
Putative causes may include:
• Genetic disorders (consider mono-zygotic twins)
• Neurodevelopment problems (age of onset)
• Neurochemical imbalances (drug misuse)
• Psychosocial stressors (‘S/he was really stressed out’)
57
more clinical aspects Schizophrenia ~ clinical aspects
The course of the illness is highly variable and is influenced by the psychosocial environment of the individual.
Schizophrenia can follow a relapsing and remitting course or it can be chronic and progressive.
The chronic, progressive course occurs particularly in individuals who have a later onset of the disease.
Prevalence: total number of cases in the population at a given time divided by the number of individuals in the population
Incidence: measures the risk of developing the disease within a specified time frame ~ a month? A year? A lifetime?
58
what is the prognosis of Schizophrenia
Most common form of presentation is an initial acute episode with florid positive symptoms followed by the emergence + persistence of negative symptoms.
Studies suggest the following:
• 20% of patients with schizophrenia recover fully.
• 70% have relapsing / remitting disease.
• 10% are seriously disabled by the disease.
59
what is the classification of Schizophrenia?
Paranoid schizophrenia
Catatonic schizophrenia
Simple schizophrenia
Undifferentiated schizophrenia
60
what is meant by Paranoid schizophrenia:
Paranoid delusions, auditory hallucinations & perceptual disturbances.
61
what is meant by Hebephrenic schizophrenia
Prominent affective changes, thought disorder, delusions and hallucinations, irresponsible and unpredictable behaviour, mannerisms and social isolation.
62
what is meant by Catatonic schizophrenia
Fluctuating psychomotor disturbances (including hyperkinesis and stupor, long periods of posturing – often bizarre postures, vivid scenic hallucinations may be present.
63
what is meant by simple schizophrenia:
Progressively strange behaviour, poor social functioning, deteriorating daily functioning and mostly negative symptoms. Overt psychotic symptoms often absent.
64
what is meant by Undifferentiated schizophrenia
```
Used when symptoms are not as stated with paranoid, catatonic or hebephrenic or when there are symptoms of more than one class present.
Residual schizophrenia: long standing negative symptoms – often the least responsive sub-type to treatment.
```
65
what are the symptoms presenting in the acute phase?
* Lack of insight (95+%)*
* Auditory hallucinations (75%)
* Ideas of reference (70%)
* Suspiciousness (66%)
* Flattening of affect (66%)
* Voices speaking to the patient (66%)
* Delusional mood (66%)
* Delusions of persecution (66%)
* Thoughts spoken aloud – echo de la pensee (50%)
66
what is the management of Schizophrenia
Management of this complex condition needs to be holistic for optimal response to ensure the best prognosis.
The following components should all be addressed:
• Psychological
• Social
• Emotional
Pharmacological management should be considered as a first-line treatment intervention in all cases but accounts for only 5% of the healthcare costs associated with schizophrenia.
67
antipsychotics
* antipsychotic response after 2 - 4 weeks
* equal efficacy (60%) against positive symptoms
* Second Generation Antipsychotics; SGAs initially thought to show greater efficacy against negative symptoms
* Clozapine is the only antipsychotic licensed for treatment resistant illness
68
what is meant by dopamine theory
Increased dopaminergic neurotransmission is a pathogenic factor of schizophrenia
Consider L-Dopa, amphetamines, LSD etc
69
dopomine d2 blockade
Antipsychotic effect
70
what drug is Striatum
```
Dopamine (D2) drug
• Extrapyramidal side effects:
» parkinsonism
» dystonia
» akathisia
• Risk factor for tardive dyskinesi
```
71
Dopamine (D2) blockade
| (Tuberoinfundibular pathway) Hypothalamus:
```
• Hyperprolactinaemia
» amenorrheoa
» galactorrheoa
» gynaecomastia
» sexual dysfunction
» Increased propensity for osteoporosis
```
72
name some of the first generation antipsychotics
* chlorpromazine
* haloperidol
* trifluoperazine
* sulpiride
* Depot preparations~ flupenthixol, fluphenazine, haloperidol decanoate etc
73
Name second generation drugs of Antipsychotics
Clozapine 1990*
• Risperidone 1993
• Sertindole 1996* Re-introduced 2002, 2005
• Olanzapine 1996
• Quetiapine 1997
• Amisulpride 1997
• Zotepine 1998 ~ Japan 1982!, Germany 1990
• Ziprasidone 2001
• Risperidone depot 2002
• Aripiprazole 2004
• Paliperidone** 2006
• Asenapine 2009
• Iloperidone 2009
• Lurasidone 2010
• Brexpiprazole*** 2015
• Cariprazine 2015
74
what is meant by Selective dopamine D2 blockade
```
Variable receptor occupancy of 5HT-2A 5HT-1A
5HT-2C and Alpha-1 sub-types
• Fewer or no EPSEs
• Less or no hyperprolactinaemia
• except risperidone and amisulpride
```
75
what are the Predictable adverse effects Type A (Augmented)
* predictable from pharmacology of drug
* common
* dose-dependent
* decreased severity with time
* high morbidity
* low mortality
76
what Predictable adverse effects for type A (augmented)
* Histamine blockade:
* Anticholinergic:
* Alpha blockade:
77
Unpredictable adverse effects Type B (Bizarre)
* not predictable from pharmacology
* not dose-dependent
* not common
* severity does not decrease with time
* low morbidity
* high mortality
78
Unpredictable adverse effects Type B (Bizarre)
79
Tardive Dyskinesia (TD)
• FGAs – incidence 10-20% first year; 4-5% per year
• Clozapine - helps improve symptoms
• Olanzapine - incidence 1% per year
• Other SGAs are all noted to cause or have the potential to cause TD
Please note that TD occurs at a higher level than baseline in patients with a diagnosis of schizophrenia that have never been treated with antipsychotics ~ i.e. TD is pathogenic for the condition.
80
Neuroleptic Malignant Syndrome (NMS)
```
• Rare - potentially fatal
• difficult to diagnose
• reports with SGAs, including clozapine
• signs and symptoms:
» temperature about 42
» labile b.p
» muscle rigidity
» Leucocytosis (with a left shift*)
» altered consciousness
» creatinine kinase
*An increased proportion of immature neutrophils
```
81
Extrapyramidal side effects EPSE’s
```
– haloperidol +++
– clozapine 0
– risperidone +(+)
– olanzapine 0 (+)
– quetiapine 0
– amisulpride +
– ziprasidone 0
– Aripiprazole 0
```
82
Hyperprolactinaemia
```
– haloperidol +++
– clozapine 0
– risperidone +++
– olanzapine 0/+
– quetiapine 0
– amisulpride +++
– ziprasidone 0
– Aripiprazole 0
```
83
ADRs with antipsychotics
```
– haloperidol +
– clozapine +++
– risperidone ++
– olanzapine +++
– amisulpride +
– quetiapine ++
– ziprasidone 0
– Aripiprazole 0
* Possible causes of weight gain: excess production of leptins feeling of fullness, occupancy of serotonergic receptors, antimuscarinic effects, excess sedation, histaminergic effects. Patient becomes desensitised to leptin so they no longer feel full
```
84
Weight gain
Weight gain over 1 year (pooled data from multiple trials)
• Olanzapine: > 6kg, > 10kg with doses of 12.5mg OD or greater
• Quetiapine and risperidone: 2kg - 3kg
• Aripiprazole and Ziprasidone: 1kg
85
how do you go about choosing an antipsychotic
- Balance between efficacy, patient tolerability, and how the proposed treatment will impact on the patient’s lifestyle.
86
what does NICE guidelines say about SGAs
• SGAs to be considered as first-line in pts newly diagnosed with schizophrenia.
• SGAs are the treatment of choice for managing an acute schizophrenic episode when discussion with the individual is impossible.
• A SGA should be considered for any individual suffering unacceptable side-effects from a conventional (typical) i.e FGA.
• A SGA should be considered for an individual in relapse whose symptoms were previously inadequately controlled.
• Changing to a SGA is not necessary if a conventional (typical) FGA controls symptoms adequately and the individual does not suffer unacceptable side-effects.
Clozapine* should be introduced if schizophrenia is inadequately controlled despite the sequential use of two or more antipsychotics (at least one of which was a SGA), at optimal dose and with compliance assured for a period of 6-8 weeks each.
87
what is meant by alternative vs complementary
* Often used interchangeably
* Important distinction
* “Alternative” is instead of
* “Complementary” is alongside or in addition to
88
what are the three major modalities
House of Lords select committee on science, complementary and Alternative medicine 2000
Three major categories:
• Physical manipulation
– Acupuncture, chiropractic, osteopathy,
• Mind/body
– Mindfulness, hypnotherapy, visualisation, yoga
• Supplementation
– Herbal, homeopathic, vitamin or trace elements
89
what is physical manipulation
Acupuncture
• Use of very fine needles inserted along specific points in the body to allow flow of ‘Chi’ energy
• In some studies efficacy was shown to be comparable to conventional drugs for both depression and anxiety
• May affect serotonin, dopamine, GABA etc levels
90
what practices are associated with physical manipulation
• Chiropractic and Osteopathy
Both modalities use manipulation of bones and joints
• Most effective against some forms of musculo-skeletal pain
• Claims have been made for positive effects beyond the musculo-skeletal system but evidence is poor.
91
what is mind and body therapies
* Essentially work by reducing the impact of exaggerated stress responses
* Reduce heart rate and blood pressure and ease respiration.
92
what is supplementation therapy
– Via herbal practitioner (and Chinese herbal)
• Can provide products made for a specific person as long as none of the ingredients are prohibited.
– Self selected (products must now be licensed under the Traditional Herbal Registration scheme
– Based on ‘Safety and Quality’
– ‘Efficacy’ can be substituted by claim for long period of use
– Potential for drug/drug interaction
93
what is st john wort?
St John’s Wort contains
hypericin (which has an anti-depressant effect) and
hyperforin (which has an antibacterial effect)
Studies appear to show that it is more effective than placebo at treating depression and as effective as standard treatments with less side effects.
Induces CYP3A4 affecting drugs such as warfarin, digoxin, anticonvulsants, oral contraceptives, SSRIs
94
what are the different forms of supplementation
– Philosophy
– ‘Like cures like’
– Increasing dilution increases potency
95
Regulation of Practitioners
```
ly Chiropractors (British Chiropractic Association) and osteopaths (General Osteopathic council) are regulated
• No statutory requirement for other practitioners
```
96
Therapeutic alliance
• Role of the therapist is crucial
• Empirical evidence suggests there is benefit
– ?placebo, does that matter?
• Use alongside conventional treatment (Complementary)
• Get the ‘buy-in’ of all concerned
97
what is the blood brain barrier
```
• Neuronal signalling requires higher level of homeostasis
– Chemical and electrical signals
• Cerebral capillary endothelial cells
– Constitute the main BBB
– Provide blood supply to brain cells
– Have tight junctions between cells
```
98
what is the function of the blood brain barrier?
• Controls the ingress of systemic substances
– Ions
– Neurotransmitters
– Macromolecules
– Neurotoxins
– Nutrients
• Levels of many of these are different in the brain v general circulation
99
Protection against neurotoxins
• Adult CNS does not have significant regenerative capacity if damaged
• ABC-energy dependent efflux transporters pump many agents out of the brain
– Endogenous molecules
– Xenobiotics ingensted in the diet
100
Intestinal v BBB diffusion?
• Poor correlation between comparative diffusion studies
• Differences in epithelium structure
– Tight junctions preclude para-cellular diffusion
– Few pinocytic vesicles
– No fenestration
• Metabolising enzymes in BBB epithelium
• Efflux mechanisms in BBB epithelium
101
Passage of drugs across BBB
• Polar molecules have generally poor CNS activity
– Unless they are actively transported
• Moderately lipophilic drugs can cross by passive diffusion
102
what is Decarboxylation of L-DOPA
* Actively transported across BBB
* L-dihydroxyphenylalanine is decarboxylated to dopamine
* Occurs during transit through the endothelial cells
enzyme which catalyzes the irreversible decarboxylation of L-Dopa and L-5-hydroxytryptophan (5-HTP), thus producing the neurotransmitters dopamine and serotonin.
103
what are the factors affecting the Blood Brain Barrier?
* Size
* Shape
* Functional groups
* Polar surface area
* Hydrogen bonding
* Ionisation state
104
how does ionistaion state affect the blood brain barrier?
• Equilibrium exists between ionised and unionised form of drug
[h+ dependent]
ionisation-----------> unionised
105
what is lipinski rule of 5
• Poor oral absorption and permeation are more likely when the drug molecule has:
– >5 H-bond donors (expressed as the sum of all OH’s and NH’s)
– M Wt > 500
– LogP > 5
– >10 H-bond acceptors (sum of all Ns and Os)
• (Substrates for biological transporters are exceptions)
106
Comparison between requirements for CNS activity v oral permeability
• CNS activity requires:
– Greater lipophilicity
– Smaller RMM
– Fewer H-bonding heteroatoms
107
what is the Filtering rule for CNS activity
```
• CNS penetration is likely if
– RMM ≤ 400
– LogP ≤5 (and ideally, >2)
– H-bond donor ≤ 3
– H-bond acceptor ≤ 7
– PSA < 90Å2
```
108
what is the average
| physiochemical characteristics for marketed CNS drugs
```
• Log P = 2.1
• RMM = 310
• O + N = 4.32
– 2.12 H-bond acceptors
– 1.5 H-bond donors
• polar surface area
```
109
what is polar surface area
• Surface area (Å2) occupied by nitrogen and oxygen atoms and the polar hydrogens attached to them
• Reflective of H-bond capacity
• High tPSA values (>140) compromise oral permeability
• tPSA > 90 compromise BBB permeability
ΔLogP
110
what is meant by dose dependent response?
• Most drugs action is concentration dependent
• Concentration at site of action depends on:
– Dose administered
– Apparent volume of distribution
– ADME factors
• rate of penetration to organs
• Rate of removal from organs
111
• Would you expect lipophilic drugs to have a larger or smaller apparent volume of distribution compared with less lipophilic drugs?
Lipophilic molecules are more likely to pass through lipid bilayers and therefore more likely to leave the bloodstream and distribute to areas with high lipid density (adipose) and therefore have a higher Vd.
112
how is Diffusion is concentration dependent
* Concentration of available drug
* Plasma protein binding can affect available drug concentration
* More lipophilic = higher protein binding
113
what are ABC transporters
• ATP-binding cassette transporters
• Family of proteins involved with homeostasis of solutes
– Lipid transport between cellular compartments
– Transport of xenobiotics
• Require energy (from ATP) to translocate substrates
114
ABC transporters
• Found throughout the body
• Largest family of transmembrane proteins
• 7 subfamilies, designated A to G
– Based on structural and sequence homology
– Implicated in multi-drug resistance
• Including various cancers where tumours over-express efflux transporters
• Inhibitor drugs found to be toxic
115
what are P-Glycoprotein (Pgp) or ABCB1
• Most important transporter for drugs
• Broad substrate specificity
– Including many therapeutically important drugs
• Found throughout the body
– Gut
– Brain
• Many drugs that are substrates for Cyp3A4 are substrates
116
list some of the Drug-drug interactions
• Some drugs are Pgp inhibitors
– Erythromycin, clarithromycin, quinidine
• Digoxin in a substrate for Pgp
– Important mechanism for excretion
• Co-administration with digoxin can lead to elevated plasma levels
117
PgP (ABCB1) substrates / inhibitors
- Amitrypline, doxepin, paroxetine (substrates) verapamil is an inhibitor
- Doxorubicin, vincristine, etoposide, paclitaxel, methotrexate and cyclosporin is the inhibitor
- Corticoids: dexamethasone is the substrates and quinidine is the inhibitor
- Morphine, loperamide is the substrate and amiodarone is the inhibitor
118
what you expect Fexofenadine to penetrate the blood brain barrier
* Few CNS effects
* Substrate for P-glycoprotein
Fexofenadine (Allegra) is the only antihistamine that doesn't permeate the blood-brain barrier and therefore cannot bind to CNS histamine1 (H1) receptors
119
name some antihistamines?
- chlorphenamine
- promethazine
- diphenhydramine
120
name some side effects of antipsychotics
```
• Associated with antagonist activity at several CNS receptors
– Histamine H1
– Adrenergic α1, α2
– Cholinergic M1
– Serotonin (5-HT)
– Dopamine D2
```
121
Extrapyramidal side effects
• First reported in 1944
– for reserpine
– 1st drug for hypertension
– Had sedative effects
• Physical symptoms, including
– Tremor
– Slurred speech
– Akathesia (restlessness)
– Dystonia (muscle spasm)
– Dyskinesia (involuntary muscle movement)
• Caused by dopamine blockade or depletion in the basal ganglia
122
what is the possible mechanism of Extrapyramidal
• Imbalance between dopaminergic and cholinergic neurotransmission
123
Extrapyramidal and antipsychotic drugs
• Common amongst all early drugs
• Clozapine (1972) had lower incidence of EPS
– Described as ‘atypical’ antipsychotic
124
SSRIs
* Arvid Carlsson developed 1st SSRI, zimelidine
* From 1st generation antihistamine, brompheniramine
* Caused unacceptable side effects (paralysis)
125
Fluoxetine
* Developed from diphenhydramine
| * Selective serotonin reuptake inhibitor?
126
Haloperidol
* Replacement of the ester with an alcohol group abolished analgesic activity
* Synthesis of 100’s of analogues produced Haloperidol
* Potent tranquiliser, many side effects
* Haloperidol blocks dopamine receptors
127
Developments from Haloperidol
* Some derivatives acted by modulating dopamine receptors in the central chemoreceptor trigger zone
* Needed something that acted outside of the BBB
* Avoid extrapyramidal side effects
* Domperidone – strong antiemetic, minimal central effects
* Risperidone – antipsychotic, fewer extrapyrimidal effects
128
list Atypical antipsychotics
* Clozapine (1960) had fewer EPS
* Is the link between EPS and antipsychotic activity inevitable?
* Has heterogenous receptor-binding activity
* Mainly D2 and 5-HT2 activity
* Combination of activity thought to be reason for lower EPS incidence
129
Are ‘atypicals’ better?
* Evidence suggests that they all induce EPS
* To differing extents
* Some studies have attempted to calculate numbers needed to harm
130
Metabolic side effects of antipsychotic drugs
* Weight gain
* T2DM
* Cardiovascular disease
* Associated with classic and atypical a’psychotics
* Appears to be associated with H1 receptor blockade
131
risk- benefit judgment
* Drugs act in a highly complex and sensitive organ
* Brain has evolved mechanisms for homeostasis
* We design drugs to overcome the barriers
* Any surprise that there are adverse effects?
132
what is meant by monoamine hypothesis?
states that depression is a result from deficiency in one or more of the 3 monoamine: serotonin, norepinephrine , and dopamine
the hypothesis also states that monoamine depletion could also cause postsynaptic receptors to up-regulate thus leading to depression
the monoamine hypothesis of gene expression suggests that there may be an abnormally functioning gene that is responsible for causing depression
133
what are the 5 different classes of antidepressants?
SSRIs - selective serotonin re-uptake inhibitors
SNRIs- seretonin/norepinephrine re-uptake inhibitors
TCAs- tricyclic antidepressants
MAOIs- monoamine oxidase inhibitors
atypical antidepressants
134
how do antidepressants work?
the serotonin is synthesised from the amino acid Tryptophan by serotonergic neurones and is stored in vesicles awaiting regulating release on the side. norepinephrine neurone is synthesised from the amino acid Tyrosine by noradrenergic neurone and is also stored in vesicles awaiting for release.
when serotonin and norepinephrine gets released they begin to stimulate the receptors and at the same time they are being transported from the synapse back to their neurones in a process called re-uptake
serotonin is reabsorbed by serotonin transporter and norepinephrine is reabsorbed by norepinephrine transporter
when they get back reabsorbed back into their neurones they're partially repackaged into synaptic vesicles and partially broken down into inactive metabolites by an enzyme monoamine oxidase
135
how do SSRIs work?
inhibits the re-uptake of serotonin and they accomplish this by blocking serotonin transporter. this results in increased levels of serotonin available to bind to post-synaptic receptors.
beside being used for depression, SSRIs can be used for other psychiatric disorders such as generalised anxiety, PTSD, and obsessive compulsive disorder.
136
name SSRIs drug ?
examples Citalopram/ Escitalopram/ Fluoxetine/ Fluvoxamine/ Paroxetine/ Sertraline
137
why does it take weeks to see results?
people with depression, the G proteins tend to cluster in the patches of the brain cell membrane rich in cholesterol called lipid rafts. when stuck on these rafts, G-proteins lack access to a molecule called cAMP which is necessary to work and transmit signals of serotonin. later it was also discovered that SSRIS also tend to build up in these lipid rafts which result in gradual movement of G- proteins out of the raft towards regions of the membrane where they are able to function better.
138
what are the common side effects of SSRIs
insomnia, erectile dysfunction irritability
| abrupt withdrawal can cause nausea and vomiting
139
How do SNRIs work?
they work by inhibiting re-uptake of serotonin via inhibition of serotonin transporter. what makes them different is that they inhibit norepinephrine transporters. this leads to both an increase in serotonin and norepinephrine which they are then able to bind to the post-synaptic receptors
SNRIs can be used for depression, anxiety and panic disorders however unlike SSRIs, SNRIs has also been shown to be effective in reducing pain associated fibromyalgia as well as other pain caused by neuropathy.
it is thought SNRIs to be related to enhanced noradrenergic activity within the central nervous system
140
name SNRIs drugs ?
Venlafaxine
Desvenlafaxine
Duioxetine
Levomilnacipran
141
what are the side effects associated with SNRIs?
similar to SSRIs but additionally may increase heart rate and heart rate
142
how do Tricyclic antidepressants work?
TCAs were found to primarily inhibit the re-uptake of both serotonin and norepinephrine by blocking both their transporters
however different TCAs such as Desipramine are more selective inhibitors of norepinephrine than serotonin transporter
TCAs may also block other receptors such as alpha receptors, histamine receptors and muscarinic receptors. blockade of these other receptors is thought to be responsible for their side effects more than their antidepressant activity
TCAs are mainly used for depression however due its broad mechanism of action they can treat other medical problems. for example Amitriptyline and Nortrityline can be used for the treatment of migraines prevention as well as neuropathic pain . TCAs such as Doxepin can be used for the treatment of insomnia
143
name some TCAs
```
Amitriptyline
Amoxapine
Doxepin
Desipramine
Imipramine
Clomipramine
Maprotiline
```
144
list some of the side effects associated with TCAs?
inhibition of alpha receptors leads to orthostatic hypotension and dizziness
inhibition of histamine receptors leads to sedation and inhibition of muscarinic receptors leads to anticholinergic effects such as blurred vision, dry mouth, constipation and urinary retention
TCAs also block cardiac sodium channels and produce similar effects to anti-arrhythmic agents such as Quinides. this can lead to cardiac conduction abnormalities
145
what is monoamine oxidase?
it is a mitochondrial enzyme that degrades monoamines such as serotonin and norepinephrine
it exists in 2 subforms: subtype A and subtype B which are differently distributed in tissues such as brain, gut, liver.
Subtype A prefers to metabolise serotonin but will also metabolise norepinephrine and dopamine
Subtype B prefers to metabolise Dopamine. this is why the inhibition of subtype A is thought to be responsible for antidepressants effects of majority of MAOIs
146
what is the MoA of monoamine oxidase inhibitors?
it inhibits the activity of MAO enzyme preventing the breakdown of monoamine neurotransmitters. this leads to increasing their availability
147
name MAOIs drugs ?
Phenelzine
Isecarboxazid
tranylcypromine
these are all irreversible inhibitors of both MAO subtype A and subtype. this makes it an effective treatment for depression
148
name a MAOI drug that is specific in targeting MAO subtype B?
Selegiline is selective to subtype B and therefore has been shown to be effective for the treatment of parkinson disease which results in depletion of dopamine. they are usually used as a last choice because MAOIs shows high incidence of drug-drug interaction but also drug-food interaction
149
what is the problem with MAOIs and food interaction?
MAO enzymes are present in the gut and they play an important role in the breakdown of monoamine ingested in food. the problem arises when inhibited MAO enzymes cant metabolise thyramine which is contained in foods that have aged/ fermented.
a build up of thyramine is taken up into the synaptic nerve terminal where it acts on the catecholamine releasing agent. the release of large amounts of catecholamine cause by thyramine leads to hypertensive crisis and potentially a stroke. people who are prescribed MAOIS must be educated about thyramine rich foods such as aged cheese and cured meat.
150
what is atypical antidepressants?
this class includes agents that have actions at several different sites and thus doesn't fit into any one class. examples include Bupropion/ Mirtazapine/Trazodone/Nefazadone/Vilazadone/Vortioxetine.
Bupropion is a weak norepinephrine and dopamine re-uptake inhibitor. besides for treating depression it is also effective in reducing nicotine cravings and withdrawal symptoms
Mirtazapine is an alpha- 2 receptor antagonist so by blocking presynaptic alpha-2 receptors, Mirtazapine increases noradrenergic and serotonergic neurotransmitters. Mirtazapine is thought to have post synaptic serotonin receptor blocking activity as well as antihistamine activity which explains the sedating effects.
Trazodone and Nefazadone- their therapeutic effects is thought to be by their ability to to inhibit re-uptake of serotonin as well as block post-synaptic serotonin receptors of subtype 2a which are the bad serotonin receptors. activation of theses serotonin subtype 2a receptors is thought to contribute to depression. theses agents antagonise histamine H1 and adrenergic alpha-1 receptors which may account for their sedative effects
Vilazadone is a serotonin partial agonist re-uptake inhibitor meaning it partially stimulates serotonin receptors and it inhibits the re-uptake of serotonin
Vortioxetine-MoA is unclear but it is believed to be related to its ability to inhibit serotonin re-uptake as well as activate and block different subtypes of serotonin receptors involved in mood regulation
151
how does lithium work?
a mood stabilising drug- initially for depression but currently used for treating bipolar disorder. has a very narrow therapeutic window index meaning any changes in its dose can lead to toxicity.
MoA is unknown as a mood stabiliser but one hypothesis states that lithium inhibits the recycling of neuronal membrane inositol lipids
in inositol lipids pathway, G-proteins coupled receptors such as serotonin receptors activate phospholipase-C which cleaves PIP-2 to the signalling molecule DAG and IP3
IP3s action is terminated by conversion to IP2. At this point the enzyme inositol phosphatase comes around and dephosphrorylates IP2 to IP1
another inositol phosphatase dephosphrorylates IP1 to free inositol which is necessary for the regeneration of PIP.
lithium inhibits both inositol phosphatase enzyme and decreases cellular response to neurotransmitters that are linked to 2nd messenger systems.
lithium also inhibits GSK3 mimicking the Wnt protein signalling pathway. the WnT protein which are secreted glycoproteins acting as signalling molecule.
when they bind to receptors, they induce certain reactions which ultimately results in the inhibition of GSK3 which regulates processes such as axon remodelling, synapse formation
the abnormal activation of GSK3 seems to be associated with disorders such as bipolar disorder.
because lithium inhibits GSK3 directly and non-directly it is likely that this particular mechanism contributes to its therapeutic effect.
