Thread by @psycheureka

Up to 60% of individuals with schizophrenia experience persistent negative symptoms (Correll C & Schooler N et al., 2020).

These symptoms contribute more to functional impairment than positive symptoms and are often under-recognised in clinical settings.

Let’s explore the neurobiology, diagnostic challenges, and treatment strategies that guide clinician care in managing negative symptoms. 🧵👇

Defining Negative Symptoms

Negative symptoms represent deficits in normal functioning and are classified into:

• Avolition

• Anhedonia

• Asociality

• Alogia

• Blunted affect

They are distinct from depression or cognitive impairment and require targeted assessment.

Clinical Burden and Long-Term Impact

Negative symptoms predict poorer outcomes in social, occupational, and cognitive domains.

They are less responsive to standard antipsychotics and more likely to persist throughout the illness.

Avolition, in particular, is the strongest predictor of real-world disability.

Symptom Trajectory and Persistence

Negative symptoms often emerge early and persist beyond the resolution of positive symptoms.

Their course is typically chronic and poorly responsive without specific intervention.

Neural Circuitry Involved

Disrupted fronto-striatal pathways underlie the core features of negative symptoms.

Key circuits include:

• DLPFC to dorsal striatum – goal-directed behaviour

• ACC to ventral striatum – cost–effort estimation

• OFC to limbic regions – reward valuation

Glutamate and NMDA Receptor Dysfunction

Hypofunction of NMDA receptors leads to impaired GABAergic inhibition and disrupted excitatory–inhibitory balance.

This contributes to cortical–subcortical disconnection, which underpins blunted motivation and hedonic tone.

Dopamine D3 Receptors in Motivation and Reward

D3 receptors are densely expressed in the mesolimbic system and modulate mood, cognition, and social behaviour.

Agents with D3 activity (e.g. cariprazine) have shown benefit in targeting primary negative symptoms.

Primary vs Secondary Negative Symptoms

Primary symptoms are intrinsic to the illness.

Secondary symptoms may result from:

• Positive symptoms

• Extrapyramidal side effects

• Depression

• Environmental deprivation

Distinguishing between them is essential for accurate treatment planning.

Assessment Strategies

Validated scales include:

• Brief Negative Symptom Scale (BNSS)

• Clinical Assessment Interview for Negative Symptoms (CAINS)

• NSA-16 or PANSS Negative Subscale

Structured assessments are critical for evaluating treatment response and clinical trials.

Pharmacological Interventions

• Cariprazine: partial D3/D2 agonist with robust evidence from RCTs

• Amisulpride (low dose): efficacy in treating primary negative symptoms

• Adjuncts: N-acetylcysteine, modafinil, minocycline in selected cases

• Neuromodulation: rTMS and tDCS targeting DLPFC show emerging benefit

Avolition as a Central Node

Network models identify avolition as the most interconnected and impairing negative symptom.

Targeting motivation and behavioural activation may offer the greatest real-world benefit.

Summary

Negative symptoms are central to the functional disability associated with schizophrenia.

They require active screening, structured measurement, and combined treatment strategies tailored to symptom type and severity.

Want to learn more about the neurobiology, clinical assessment, and management of negative symptoms in schizophrenia?

Read the full article, “Negative Symptoms in Schizophrenia – A Review of Neurobiology, Diagnosis and Management,” on The Psych Scene Hub:

psychscene.co/4mt7tWY