Why do some patients respond poorly to antipsychotics despite adherence and diagnosis?

Emerging research points to muscarinic receptor dysfunction. M1 and M4 receptors are densely localised in memory circuits, especially the hippocampus, amygdala, and neocortex, where they modulate synaptic plasticity and cognitive processes.

Could a missing cholinergic signal explain what dopamine alone cannot?

1/13 🧵 Some have proposed a muscarinic receptor-deficit subtype of schizophrenia (MRDS), characterised by reduced cortical and hippocampal CHRM1 and CHRM4 expression.

While not yet a clinical diagnosis, the anatomical groundwork for this concept is supported by receptor mapping studies.

2/13 🧵

During fasting, the brain shifts to β-hydroxybutyrate (BHB) metabolism.

BHB is not just a fuel source; it upregulates brain-derived neurotrophic factor (BDNF), activates autophagy, and supports synaptic maintenance.

These changes may reduce neuroinflammation and support mood and cognitive stability.

1/15 🧵 Once glycogen stores are depleted, the brain shifts from glucose to ketones like β-hydroxybutyrate (BHB).

BHB is not just a fuel; it’s a signalling molecule that activates pathways associated with neuronal growth and resilience.

2/15 🧵

A 2010 study found that 25% of obese individuals with serious mental illness met criteria for Night Eating Syndrome (NES), a rate significantly higher than in the general population.

This has significant implications for psychiatric care, yet remains under-recognised.

1/12 🧵 This study (Lundgren et al., 2010) examined 68 overweight or obese, treatment-seeking adults with serious mental illness (SMI), including schizophrenia, bipolar disorder, schizoaffective disorder, or major depression.

The goal is to determine the prevalence of Night Eating Syndrome (NES) and Binge Eating Disorder (BED).

2/12 🧵

How does pregnancy reshape the brain?

One study found structural changes are so distinct that it could predict pregnancy with 95.6% accuracy, just by looking at brain scans.

Here’s why it matters for understanding peripartum mood disorders, attachment, and psychiatric vulnerability.

1/14 🧵 Hormones trigger brain-wide shifts.

Estrogen and progesterone surge rapidly in early pregnancy.

This isn’t just systemic but neuroplastic.

These hormonal cascades remodel the maternal brain to prepare for caregiving, bonding, and attunement.

2/14 🧵

Experienced psychiatrists don’t merely assign diagnoses.

They construct dynamic formulations.

Diagnosis begins the process.
Formulation guides the intervention.

Here’s how hypothesis-driven thinking reshapes psychiatric practice.

1/12 🧵 Too often, we diagnose forward:

Symptom → Label → Treatment

But when treatment fails, is the drug at fault—or was the label flawed?

Diagnosis must be more than categorisation.

It’s about understanding why symptoms exist.

2/12 🧵

Why do some patients feel unsafe in stable relationships?

In Borderline Personality Disorder (BPD), what looks like ‘attention-seeking’ is often an automated survival pattern, deeply encoded through implicit memory and prediction mechanisms.
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1/13 🧵 Familiar instability becomes the norm.

Patients with BPD often experience early environments marked by unpredictability, abandonment, or emotional neglect.

Over time, the brain learns: instability = safety.

Stability feels foreign, not soothing.

2/13 🧵

Antidepressant withdrawal is not rare.

Up to 56% of patients experience withdrawal symptoms when stopping antidepressants. Nearly half of those describe them as severe (Davies & Read, 2019).

Yet antidepressant withdrawal is often under-recognised in clinical practice, despite clear evidence of neuroadaptive changes, serotonergic dysregulation, and symptom trajectories distinct from relapse.

1/13 🧵 Withdrawal ≠ Relapse.

Discontinuation symptoms may mimic the return of illness, but the mechanisms are distinct:

● Synaptic serotonin drops

● Downregulated receptors remain hypoactive

● Dysregulation of downstream GABA/dopamine systems

2/13 🧵

Up to 40% reduction in depression risk has been observed with adherence to anti-inflammatory diets like the Mediterranean diet, according to the PREDIMED study.

Emerging research links dietary patterns to neuroinflammation, neurotransmitter synthesis, and gut–brain signalling.

Here’s what clinicians need to know about nutritional strategies in psychiatric care, from gut microbiota to therapeutic nutrients. 🧵👇 The Gut–Brain Axis and Mental Health

The GI tract hosts 100 trillion microbes influence mood, cognition, and stress regulation.

Disruptions (e.g., from a Western diet) are associated with depression and anxiety.

Some strains produce neurotransmitters (e.g., serotonin precursors).

Which patients with schizophrenia are at the highest risk of suicide?

In a 3-year pan-European study of 8,871 outpatients, the suicide attempt rate was 4.3%, with key predictors including prior attempts, depressive symptoms, prolactin-related side effects, male gender, and prior hospitalisation.

1/12 🧵 Lifetime suicide attempts increased future risk nearly fivefold (OR: 5.2), and suicide attempts in the 6 months prior raised risk 3.7× compared to none.

This finding reinforces the need for detailed longitudinal histories.

2/12 🧵

Over 50% of psychotropic medications are metabolised by CYP450 enzymes, many of which are genetically polymorphic.

This genetic variability explains why individuals differ significantly in drug response, tolerability, and plasma levels.

Here’s what you need to know about CYP pathways, phenotypes, clinical indications, and how to integrate testing into psychiatric practice. 🧵👇 What Is Pharmacogenomics?

Pharmacogenomics examines how genetic variation influences drug metabolism, receptor activity, and transport.

It informs dose adjustment, medication selection, and risk stratification, especially in psychotropics. (Hicks et al., 2015; Foulds et al., 2016)

Can probiotics reduce neuroinflammation in autism?

A small 2018 RCT in Egypt (Shaaban et al.) found autistic children taking probiotics had ~66% lower plasma myeloperoxidase (MPO) levels than those not on probiotics (1054 vs. 3161 pg/mL; p = 0.0009).

Findings are promising, but not yet generalisable.

1/13 🧵 MPO is a marker of neutrophil-driven inflammation.

It catalyses the formation of hypochlorous acid (HOCl), a reactive species linked to tissue damage and oxidative stress.

2/13 🧵

An EEG study reveals that individuals with ADHD exhibit increased theta and alpha power, coupled with decreased beta power, indicating impaired attention regulation and executive control (Michelini, 2022).

These patterns reflect the same brain dynamics underlying overthinking: intrusive, uncontrolled, and cognitively taxing thought loops.

1/11🧵 Overthinking is not a diagnosis, but a symptom that crosses diagnostic boundaries.

In ADHD, anxiety, depression, PTSD, and bipolar disorder, it can signal cognitive dysregulation within core brain networks.

2/11 🧵

Over 46% of the population carries the DRD2 A1 allele, which is linked to lower dopamine receptor density and increased risk of impulsive and compulsive behaviours (Blum et al., 2022).

Blum et al. (1995) found it could predict Reward Deficiency Syndrome behaviours, such as substance use and overeating, with up to 74.4% accuracy.

How does this genetic profile shape behaviour? RDS is not a single disorder.

It’s a transdiagnostic spectrum of addictive, impulsive, and compulsive behaviours driven by hypodopaminergia—low tonic dopamine tone in mesolimbic circuits.

The phenotype may vary, such as substance use, gambling, and overeating, but the dopaminergic dysfunction is often shared.

Cognitive impairment is present in up to 80% of patients with schizophrenia, affecting attention, memory, and executive function (Saperstein & Kurtz, 2013).

These deficits are central, not peripheral, to functional outcomes.

Here's what clinicians need to know about diagnosis, monitoring, and treatment based on updated schizophrenia guidelines.👇🧵 Metabolic and Prolactin Monitoring

Guidelines recommend considering baseline and regular monitoring for:

• Metabolic parameters

• Prolactin levels

• Extrapyramidal symptoms

• Cognitive status

Failure to monitor contributes to treatment resistance and poor adherence.

Studies show that 50–75% of people with PTSD also experience chronic pain.

In PTSD, the brain’s defence systems become sensitised.
This lowers the threshold for detecting threat, whether emotional or physical.

Psychological pain and bodily pain begin to merge.

1/14 🧵 Meanwhile, 20–37% of those with chronic pain meet the criteria for PTSD.

(Scioli-Salter et al., 2015)

2/14🧵

Up to 90% of patients with ADHD experience at least one comorbidity—ranging from anxiety to substance use disorders.

These overlaps complicate diagnosis and treatment, making clinicians need to recognise and address them effectively.

Here are 10 key ADHD comorbidities and evidence-based strategies to navigate them 👇🧵 1. Behavioural Disorders & ADHD

Oppositional Defiant Disorder (ODD) overlaps with ADHD (irritability, reactivity) but includes defiance and vindictiveness.

→ Mild: Start with stimulants (e.g., methylphenidate).
→ Moderate-severe: Add CBT or parental training. 
→ Severe: Consider risperidone.

Conduct Disorder (CD) involves persistent aggression or deceit, risking antisocial outcomes.

→ Combine stimulants with therapy. 
→ Severe: Use SSRIs or antipsychotics like risperidone.

The brain doesn't just react to medications. It adapts.

Opponent Process Theory (OPT) explains how tolerance, withdrawal, and paradoxical effects emerge.

One of the most under-taught concepts in psychopharmacology.

🧵1/15 In clinical training, we learn what medications do to the brain. 

But we rarely ask what the brain does in response to the medication. That’s the core question OPT helps answer.

🧵2/15

Even after months of abstinence, drug cues alone can trigger dopamine surges in the nucleus accumbens—driving relapse with no substance present (Volkow et al., 2019)​.

With each exposure, dopaminergic circuits reorganise, weakening prefrontal inhibition and reinforcing compulsive drug-seeking.

How do these neuroadaptations lock patients into addiction, and what can you do to restore cognitive control, reduce relapse, and rewire the brain? 🧵👇 Why Addiction is More Than Just Behaviour

The mesolimbic dopamine system reinforces reward and motivation. In addiction:

• VTA → Nucleus Accumbens: Heightened dopamine release → Stronger craving.

• Prefrontal Cortex Dysfunction: Reduced inhibition → Impaired self-control.

• Amygdala & Hippocampus: Drug-related memories become deeply ingrained​.

These adaptations make patients hypersensitive to triggers, even after long periods of abstinence.

Human endogenous retroviruses (HERVs), typically dormant sequences comprising 8% of the human genome, can be activated by viral infections and implicated in schizophrenia.

HERV-W transcripts and proteins have been detected in the brain tissue and plasma of patients with schizophrenia.

Let’s explore the molecular and immune-related mechanisms through which viral infections may contribute to the pathogenesis of psychotic disorders. 👇🧵 HERVs and Schizophrenia

The HERV-W and HERV-K families are the most studied in psychosis.

HERV-W envelope proteins may be reactivated by environmental viruses, leading to neuroinflammation and neural circuit disruption.

This activation may play a role in the development of psychosis in vulnerable individuals.

KarXT (Xanomeline–Trospium) is the first FDA-approved muscarinic receptor agonist for schizophrenia.

Unlike traditional antipsychotics, it acts on M1/M4 receptors, not D2, offering efficacy without dopaminergic side effects.

Let’s break down the mechanism, trial data, and clinical impact. 🧵👇 Dopamine-Independent Mechanism

KarXT is a combination of:

• Xanomeline: a centrally acting M1/M4 agonist and

• Trospium: a peripheral muscarinic antagonist that doesn’t cross the BBB

It reduces psychotic symptoms without blocking D2 receptors.

Clozapine is the only antipsychotic with proven efficacy in Treatment-Resistant Schizophrenia (TRS), yet its use is often significantly delayed, sometimes by 5 years or more.

Despite more than 50% of community-treated patients meeting criteria for treatment resistance, many never receive it.

Here’s what clinicians need to know to identify treatment resistance early and optimise the use of clozapine in practice. 👇🧵 Defining Treatment Resistance

• Treatment resistance is often defined as non-response to two antipsychotic trials of adequate dose and duration.

• In the STAR algorithm, response rates drop significantly after failure of the first medication.

• Delays in initiating clozapine reduce the likelihood of remission.

Psych Scene Tip: TRS should be identified early and explicitly to prevent ineffective polypharmacy.