Challenges in Treatment - Write

TRD McIntyre, et al., 2023

Research concepto; failed response after two or more adequate trials in a curren episode. Associate with poorer outcome,s higher mortality rates and lower quality of life of life.

Difficult-to-treat depression McIntyre, et al., 2023

Reflects the complexity, chronicity and impact of this diagnosis. Emphasize sperosnalized treatment. Accordance to Rush et al., 2018 mode. )

low risk

risk‑stratification categories

• Single episode

• Continue treatment 6–9 months after remission

high risk

risk‑stratification categories

• More than one episode

  • Continue treatment ≥1 year

high recurrent risk

Risk stratification categories

• 5+ episodes, or 2 episodes in 2 years

• Consider long‑term maintenance treatment

comorbidities, chronic depression, poor functioning, long current episode

Unfavorable predictors for depression according to STAR-D

(Warden et al., 2007)

structure of CBT

This therapy is:

present focused

directive and structured

time limited

aim - build self-help skills

cogn

cognitive mechanisms

automatic thoughts - spontaneous and accessible and believable

intermediate thoughts - rules of living, conditional (“if…then…”)

cognitive maintenance of depression

Vulnerability - dysfunctional scheme

Trigger events activate this (turning it into a vicious cycle)

Leads to:

negative thoughts

cognitive distortions

behviaoural responses

consequences

antidepressant caution

specific risk - Tricyclic antidepressants and MAOIs

did not improve bipolar depression

did not speed recovery

higher risk when not combined

Psychotherapy improved recovery (1.58 x more likely)

cognitive impairment

Impairment in mental processes involved in learning, retrieving info, understanding , planning, resolving and making decisions.

They are heterogeneous across patients and are hard to discern from illness or medication effects.

Cognitive Remediation Therapy

Cognitive impairment is an underrated persistent issue within affectivee disorders.

(Millet & Burdick et al., 2021)- resiliency course

This type of of therapy targets persistent cognitive deficiencies.

Findings are preliminary (we need larger (RCTs)

Promotes metacongition (knowledge and regulation) and emphasizes strategy use

there is promising evidence, yet no replication AniA

Animal Models

Are used for exploratory and developmental reasons, because regulations demand them to fulfill requirements, to investigate underlying mechanisms and are demanded by the public.

Have a low-construct validity (extent to which a tolls measures a theoretical/abstract concept).

validity of a procedure depends on the objectives of the experiment.

Disadvantages:

• Do not capture subjective epxiernces

• Psychological disorders are language based

• No biormarkers

• Cross-sectional analysis

Treatment Resistant Depression

Focuses on an acute biological

Research definition

Failure of two or more adequate trials in current episode

Approach is many biomedical with a categorical endpoint (remission or not)

Difficult-to-treat depression

It is a collaborative concept, representing a chronic illness model

Approach: biopsychosocial, capability approach, recovery movement, optimizing symptom control, minimizing impact of symptoms.

Endpoint is dimensional

Assessment is 3D:

Uses a 3D assessment model (McAllister-Williams et al., 2020):

• person factors (genetics, trauma, etc)

• illness factors (early onset, chronicity, comorbidity)

• treatment factors (previous response, number/type, etc.)

Ketamine

A substantial proportion of patients with depression fail to respond to monoaminergic antidepressants, highlighting the need for treatment targeting alternative mechanisms. This form of treatment provides an antidepressant effect through glutamatergic modulation and synaptic plasticity enhancement, making it a key therapeutic option for TRD and DTD.

McCloud et al., 2015

It is a meta‑analysis of RCTs of single‑dose IV ketamine in bipolar depression. It found large, rapid antidepressant effects within 24 hours, with benefits lasting up to 7 days. The study is important because it demonstrates that glutamatergic mechanisms can produce rapid mood improvement. However, it is limited by very small trials, short follow‑up and restricted samples, meaning the evidence is promising but preliminary.

Disadvantages

• effect is rapid and short-lived

• conclusions are limited due to small amounts of usable data

  • small n - underpowered

  • no active placebo

  • heterogeneous deign

• Evidence base is too small and too low-quality to draw reliable conclusions

Substance abuse and affective disorder

Addiction and mood disorders—particularly bipolar disorder—show a strong bidirectional relationship. Individuals with bipolar disorder have markedly higher rates of substance use disorders (SUD), while substance misuse worsens course, relapse risk, suicidality, and treatment adherence. This suggests addiction is not merely comorbid, but a major factor influencing prognosis and management.

self-medication hypothesis

According to this hypothesis, individuals with a mood disorder may employ substances as a coping mechanism to address their mood dysregulation or symptoms.

For instance:

alcohol → anxiety or agitation

cananbis → calm mood

sedatives → distress

stimulants → counter depression re

Challenge of hypothesis: Although SUD worsen long-term instability in BD, a study shows (Stakowski et al., 2000) that 75 % of people with bipolar disorder do not change their alcohol consumption during a manic episode.

reward pathway

Possible underlying mechanism of addiction and affective disorders

Addictive substances dysregulate reward-learning mechanisms by generating dopamine signals larger of aster than natural rewards.

higher risk of suicide, poorer adherence to treatment, poorer outcomes, higher relapse rates

Effect of comorbidity SUDs

Judd et al., 2002, 2003

Depressive symptoms overwhelmingly dominated the symptomatic periods in both bipolar I and bipolar II disorder.

In bipolar I, 67% of symptomatic weeks were depressive

In bipolar II, depressive symptoms accounted for 94% of symptomatic weeks

FDA, 2011

Systematic review & meta-analysis

Biological efficacy of ECT is superior than Sham (ECT placebo) and medication.
ECT is more effective than meds; especially in severe depression

Support ECT as most effective acute treatment

Disadvantages:

• older trials included

• variation in ECT techniques

  • short follow-ups

Nordenksjold et al., 2012

Large observational cohort study

Predictors of ECT response:

• older adults

• more severe depression

• psychosis

• personality disorders

• inpatients respond better than outpatients

Disadvantages:

• observational (confounding factors; cannot infer causality)

  • limited generalizability

Jelovac et a., 2013

Systematic review & meta-analysis

Relapse rates for ECT

~ 27% at 3 months

~ 51% at 12 months

~ 50% at 24 months

Highly effective acutley but relapse is a major issue.

Psychedelic mechanism

activate 5‑HT2A receptors on cortical pyramidal neurons, increasing their excitability and producing a glutamate surge in the prefrontal cortex. This stimulates AMPA receptors and triggers BDNF release and mTOR signalling, which together promote synaptic plasticity.

ketamine mechanism

blocks NMDA receptors on GABA interneurons, reducing inhibition and causing a glutamate surge in the prefrontal cortex. This enhances AMPA receptor activity and initiates BDNF release and mTOR signalling, leading to rapid increases in synaptic plasticity.

personality

·      relatively stable pattern of traits for which a person manifest thinking/feeling/acting.

o   Collection of mental representations of self

o   Begins consolidating in adolescence; persists across adulthood

personality disorders

·      severe disturbance in characterological conditions associated to considerable personal and social disruption.

o   Long standing and enduring

o   Significant distress/impairment

o   Deviates from cultural expectations

o   Onset adolescence/early adulthood

Methodological challenges of psychotherapy

There are in asymmetry in reporting.

Greatest benefits seem to derive from the therapeutic alliance.

Therapy can not be blinded and there may always be an expectancy effect that a waitlist comparator can not account for.

While ADM have mandatory reports of harm, therapy doesn’t when it can lead to increased instability.

Colom et al., 2003, 2009

2 RCTs done by the same group using the Barcelona program (21 sessions) . Structured: illness awareness, prodrome detection and adherence to a long-term trajectory.

5 year follow up

Findings:

• diminshed relapse (especially manic)

• prevented manic episodes

• diminished hjopsitalisations

Relevance

• effects are durable - persisting up to 5 years

• strong evidence for pyschoeducation

Reinares et al., 2013

Narrative review comparing psychosocial interventions for Bipolar.

• Best - structured group psychoeducation

  • long-lasting effect ts

• CBT - most effective to prevent depressive spidoses

• IPSRT - useful in acutely ill patients

  • may increase time of remission

• Functional remediation - improves social and cognitive functioning

Relevance

• phase-specific interventions

• mehcnaism-specific eiinterventions

• highlight that psychosocial interventions target different pathway s

Disadvantages

NOT a meta-analysis - selection bias

effects depend on illness stage and polarity

heterogenous

small nG

Goodwin et al., 2022

Double-blinded clinical trial

single psychedelic session (psilocybin)

Active placebo

Findings:

• 25 mg psilocybin produced significantly greater reductions in MADRS at 3 weeks vs 1 mg.

• 26% were in remission at 12 weeks

• Effects were strongest in the first 3–6 weeks and attenuated over time.

• Adverse events were mostly mild/moderate and transient (headache, nausea, transient anxiety).

(disadvantage)

• blindings is questionable as 25 mg is probably recognizable (1 mg)

• Psychological support was standardised but still a potential confound.

• Industry‑sponsored (COMPASS Pathways).

• Excluded people with significant comorbidities → limits generalisability.

  • highly selected sample

Carhart-Harris et al. 2017

Open-label trial with 6 month follow-up

Produced 33% of remission at 6 months follow-up

• Some participants maintained substantial, sustained improvement.

• Qualitative reports suggested increased emotional openness and psychological flexibility.

Limitations

• open-label

• no control group

• highly selected motivated patients

• Intensive psychological support → unclear contribution of therapy vs drug

these estimates are inflated by the absence of controls and high expectancy effects.”

Elawad et al., 2021

Observational cohort-study

Predictors of higher response rates of ECT

• psychotic features

• old-age (especially w/ psychotic features)

• severe depression

• TRD

• suicidality

disadvantages:

• observational - cannot infer causality

  • heterogeneous sample

Wang et al., 2023

large prospective cohort study

Childhood maltreatment (any type) is significantly associated with the risk of depression in late-life depression.

High quality population-based evidence

Supports trauma-informed models

Disadvantages:

• self-report (recall bias)

• cannot infer causality

• UK - cannot generalize

  • confounders

Barnes et al, 2012

Retrospective cohort study

Depression ate any stage of life increases the risk of dementia - may be prodromal to dementia

Depression may be hard to diagnose - avoid polypharmacy (anticholinergic burden: cumulative negative effect of multiple medicines block ACTh - age related sensitivity)

Disadvantages:

• depression measured symptom questionnaire

• cannot separate cause from prodrome

• confounding