Sz and unipolar depression combined

Delusions

False beliefs

Skodlar et al. (2008) - Delusions across time

120 1st time Sz patient records at a Slovenian psychiatric hospital 1881-2000

Hallucinations

Vivid, clear sensory perceptions experienced in the absence of corresponding external stimulation that would produce the same effect in other people.

Luhrmann et al. (2015) - Hallucinations across cultures

Asked about hallucination of 20 people in 3 different countries with Sz and heard voices (USA, South India, West Africa)

Reichenberg (2022) - Sz cognitive function summary of meta-analyses

All aspects of cognitive function affected in Sz with good effect size.

Sz requirement A

2 or more of delusions, hallucinations, thought disorder, abnormal motor behaviour, negative symptoms

Sz requirement B

Impaired functioning for sig proportion of time since onset

Sz requirement C

Symptoms present for more than 6 months

Prevalence of Sz - Simeone et al. (2015)

0.48 per 100 people

Gender split Sz

For every 7 men that develop it, 4 women do.

Structural brain differences in Sz - Haijma et al. (2013)

Enlarged ventricles - 25% bigger

Reduced brain volume - 2% smaller - Mostly grey matter in frontal lobe.

Some white matter loss also found.

Functional brain differences in Sz

Unusual patterns of activation in PFC (sometimes overactive, sometimes underactive).

Hypothesis: frontal cortex fails to appropriately disactivate (on when should be off, off when should be on).

Sz concordance rates - Coelwij and Curtis (2018)

MZ = 48%

DZ = 17%

Risk for developing Sz is higher for…. - Stilo and Murray (2019)

• Men, sexual and gender minority groups

• Urban dwellers (mixed evidence)

• Migrants

• Social adversity in chilldhood

• Cannabis users

• Immune disorders

• Head injuries

Antenatal risk factors Sz

Obstetric risk factors:

• Pregnancy complications

• Abnormal foetal growth/development

• Delivery complications

Antenatal risk factors:

• Maternal stress

• Maternal poor nutrition

• Maternal viral exposure.

Likely that metabolic, endocrine and oxygen-related alterations to uterine environment alter foetal environment (oxygen deprivation in obstretic emergency impacts brain development).

Early life immune risk factors - Disanto et al. (2012)

Sz rates highest in people born between Jan and March (northern hemisphere). Varies around the world - seasonal viruses may explain the effect.

Exposure to viruses in general (not just seasonally) may have an effect on Sz - Canetta et al. (2014)

Levels of c-reactive protein (immune marker of infection) in amniotic fluid predict Sz later in offspring.

Reality monitoring impairments

Much poorer at judging whether a stimulus is internal or external. Functionally linked to PFC.

Genain quadruplets - Mirsky et al. (2000)

All developed Sz-spectrum disorders by age 24, but presentation and level of functioning varied. Some children were treated more favourably than others.

First generation antipsychotics

Phenothiazines. Block dopamine receptors to reduce obvious symptoms - including hallucinations and delusions.

30% don’t respond to them.

Huge side effects e.g. Tardive dyskinesia.

Second generation antipsychotics

Same effectiveness - acts on serotonin and dopamine receptors.

e.g. Clozapine, Olanzapine, Risperidone

Side effects e.g. weight gain, metabolic disorders

Relapse and maintenance of Sz antipsychotics

Help to control symptoms, but don’t cure. Maintenance doses needed, relapse possible.

20% lifetime remission rate after one episode (most people experience further episodes)

Effectiveness of CBT for Sz - Berendsen et al. (2024)

Effectiveness for general and positive symptoms found in meta-analyses of several trials at once.

But effect sizes are small to medium and not typically sustained.

Avater therapy - Craig et al. (2018)

Avatar is a brought to life version of the Sz person’s voices - avatar builds a better relationship with person, person slowly empowered to talk back to voice.

Emotion

Complex reaction pattern used to deal with a personality significant matter.

Feeling

Self-contained phenomenal experience: subjective, evaluative and independent of the sensations, thoughts or images evoking them.

Affect

Any experience, feeling or emotion.

Mood

A disposition to respond emotionally in a particular way that may last for hours, days or weeks.

What are mood disorders?

MH conditions where principal feature is prolonged, intense and persistent affective disturbance.

2 main types: unipolar and bipolar

MDD requirement A

5 of more of: depressed mood, diminished interest in activities, weight loss/gain, insomnia, hypersomnia, psychomotor agitation, fatigue, worthlessness, can’t think/concentrate, recurrent thoughts of death

MDD requirement B

Symptoms cause clinically significant distress

Other types of depressive disorder (different to MDD)

Persistent depressive disorder (dysthymia) - MDD symptoms for >2 years, any break from symptoms <2 onths. 10-20% people with MDD

Premenstrual dysphoric disorder - Symptoms present 7 days before menstruation.

Disruptive mood dysregulation disorder - Onset before 10 years (must be under 18, over 6 for diagnosis). >3x week temper outbursts, mood in between irritable. Symptoms present for >12 months.

Cog changes in MDD

Moderate decreases in processing, speed, attention, executive function, learning and memory

Beck (2008) - cognitive triad

Negative thoughts about self, environment and future.

Early life experiences lead to formulation of dysfunctional beliefs.

These beliefs are activated by stressful events in adulthood.

Remittance

Symptoms go for more than 2 months

Relapse

If symptoms reappear in a short period of time after remittance.

Recurrence

Symptoms remit for a longer time, then return

Residual symptoms

Mild symptoms that persist even after response to treatment/during remission

Peak of MDD onset across lifespan - Zisook et al. (2007)

20-30 years old

DALYS for diff MH conditions by age - Whiteford et al. (2013)

Depressive episodes have the biggest impact on DALYS.

How many affected by MDD?

6%

When do gender differences in diagnosis rates and depressive symptoms appear - Salk et al. (2017)

Diagnosis rates: at 15, women 3x more than men. At 20, women 2x more likely than men.

Depressive symptoms: Highest gender split at 15-20

Why are there gender differences in MDD?

Sex-gender specific characteristics.

Sex: females have larger adrenal glands, secrete more cortisol in response to stress.

Gender: Societal gender roles often result in women facing more stressors than men. Men respond to more stressors like achievement pressure, women find interpersonal conflict more stressful.

Heritability of MDD

35%

MZ twin of an MDD person is 2x more likely to develop MDD than DZ twins.

Social drift hypothesis

MH conditions contribute to a gradual downward spiral - compounded by systemic stigma, discrimination and marginalisation based on MH status.

Recorded how many stressful life events someone had and probability of developing depression - Kendler et al. (2005)

A particular gene involved in serotonin transport may confer risk of depression. Increased risk of depression only manifests after 1 stressful life event.

Meta-analysis of 31 datasets, genotyped for 5-HTTLPR - Culverhouse et al. (2018)

No sig interaction between stress and 5-HTTLPR genotype.

Stress response in MDD

In MDD, HPA axis negative feedback is inhibited and ‘off-switch’ of cortisol is broken = keeps producing cortisol.

Also chronically elevated levels of stress responses and immune activation affects CNS = alters neural plasticity, connectivity and transmission.

May explain structural and functional brain differences observed.

Brain regions with a smaller volume in MDD

Caudate nucleus, thalamus, putamen, globus pallidus, hippocampus, frontal lobe, orbitofrontal cortex, gyrus rectus

Changes in brain activity in MDD

1. Affective-salience circuit - amygdala hyperactivated and hyperconnected with dorsal ACC and insula = increased salience of negative info

2. Default-mode network - hyperconnectivity = higher levels of self-directed thoughts

3. Fronto-parietal circuit - hypoconnectivity = difficuties in goal-directed tasks. Underactivity at rest and for negative stimuli = lack of top down control over negative thoughts?

Antidepressants

Usually take for min 6 months

• SSRIs (serotonin) e.g. fluoxetine

• Tricyclic antidepressants (serotonin, norepinephrine) e.g. amitriptyline

• Monoamine oxidase inhibitors (serotonin, norepinephrine, dopamine) e.g. phenelzine

Review of 21 varieties of SSRIs and TCAs - Cipriani et al. (2018)

CBT for MDD more effective than doing nothing (moderate to large effect size)

Problems with monoamine hypotheses of depression

1. Rapid change to 5-HT conc not consistent with delayed onset of symptom relief

2. Lowering 5-HT conc in brain doesn’t induce depression in people without MDD

3. Low-term antidepressant treatment downregulates total 5-HT conc in brain

4. No evidence of problems with monoamine dysfunction in brains of people with MDD

Other possible mechanisms of serotonin-targeting drugs

Delay in symptom relief may suggest that drugs are stimulating neurogenesis in key areas of brain.

Stress causes decrease in brain-derived neurotrophic factor (BDNF) = causes disruption of intracellular signalling, and number and function of synapses.

• Antidepressants may help reverse some changes by raising BDNF = increasing plasticity

CBT for depression

Helps us recognise relationship between thoughts, behaviours and emotions.

16-20 structured sessions over 3-4 months

• Identify negative, distorted thinking patterns that cause depression

• Train skills to test and challenge negative thoughts and assumptions

• Behavioural activation - increases positive activities that increase pleasure/mastery

• Stress and relaxation techniques

Collaborative empiricism - patient and therapist become co-investigators in ascertaining goals for treatment and investigating the patient’s thoughts.

Effectiveness of CBT for depression - Cuijpers et al. (2016)

CBT more effective than doing nothing (moderate to large effect size).

Marginally more effective than medication alone

Possible slight advantage of combining CBT and antidepressants

Health economics modelling in USA - Ross et al. (2019)

CBT and second-generation antidepressants equally cost-effective over 5 years.