Guidelines for Negative Symptoms in Schizophrenia

Finally, answers for the most disabling symptoms of schizophrenia

STUDY: Mølgaard SN et al, Nordic Journal of Psychiatry 2026

STUDY TYPE: Clinical practice guideline (Danish Multidisciplinary Psychiatry Group)

FUNDING: Independent

Background

Negative symptoms cause more disability in schizophrenia than the psychosis itself. They include:

• Emotional blunting
• Lot motivation
• Social withdrawal and Impaired interactions
• Reduced thought and speech
• Poor self-care
• Cognitive problems

These symptoms help define schizophrenia. They separate it from other psychotic disorders like schizoaffective, delusional disorder, and psychotic mood disorders.

Denmark’s Multidisciplinary Psychiatry Group created a national guideline for these symptoms.

Summary

First, assess negative symptoms carefully. They recommend The Brief Negative Symptom Scale, which covers five core areas:

1. Anhedonia (lack of pleasure)
2. Asociality (lack of socializing)
3. Avolition (lack of motivation and activity)
4. Alogia (reduced speech)
5. Blunted affect (lack of facial expression)

Involve the family in that assessment.

Next, look for other causes and address them: Undertreated psychosis, depression, sedating medications, or extrapyramidal side effects from antipsychotics that reduce activity and expression.

If they are on a first-generation antipsychotic, consider switching to a second-generation one. Cariprazine, amisulpride, and clozapine have some evidence to reduce negative symptoms directly, while other antipsychotics are only known to do so indirectly (by treating positive symptoms).

Depression vs Negative Symptoms

Ask whether core depressive or negative symptoms predominate, and look for distress. Patients are more likely to complain of depression than negative symptoms, while the family is more likely to notice negative symptoms. However, patients are often bothered by the downstream effects of negative symptoms, like loneliness or unrealized life-goals.

If depression predominates, add an antidepressant (SSRIs, duloxetine, mirtazapine, and vortioxetine have evidence for negative symptoms and depression), switch to an antipsychotic with antidepressant properties, or add cognitive behavioral therapy.

Treating Core Negative Symptoms

For persistent primary negative symptoms, options include

1. Add-on antidepressant treatment even without depression
2. Modafinil (or armodafinil, which has steadier levels throughout the day)
3. Transcranial magnetic stimulation

Cognitive remediation, social skills training, CBT for psychosis, and exercise are also recommended add-ons. Avoid THC (cannabis), which worsens negative symptoms.

All of the recommendations in the paper were “conditional,” based on “modest evidence.” Dietary supplements, oxytocin, anti-inflammatory agents, oxytocin, naltrexone, and NMDA-targeting agents (eg, memantine) were not recommended due to weak evidence. Among supplements, I’d say that ginkgo and sarcosine have the best evidence, but the choice depends more on personalization.

A Personalized Approach

This is my take. The strategies reviewed in these guidelines have weak evidence and small effect sizes, so it is somewhat arbitrary to elevate a few to the top tier. Instead, personalize the choice based on comorbidities they address. Negative symptoms don’t occur in isolation:

1. Tardive dyskinesia or vascular disease: Ginkgo (egb 761)
2. Low energy or sleep apnea… Modafinil
3. High cholesterol… Omega-3
4. Obesity or irritable bowel syndrome… Probiotics
5. Folate deficiency, MTHFR abnormality, or inflammation…. l-Methylfolate
6. Arthritis… Curcumin or an NSAID (celecoxib)
7. Menopausal women and women with osteopenia: Raloxifene (an estrogen receptor modulator that treats negative and positive symptoms in perimenopausal schizophrenia)
8. Acne… Minocycline
9. OCD… Lamotrigine, topiramate, or memantine (all may help negative symptoms)
10. Hypertension, insomnia, irritability… Clonidine or guanfacine
11. Significantly low testosterone or vitamin D… Treat that
12. Meth or cocaine use… Citicoline

The options above all worked in at least one placebo-controlled trial for negative symptoms, and most passed in a meta-analysis.

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

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