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 built a national guideline spanning children through adults, based on a systematic review of international guidelines and recent meta-analyses.
Summary
First, assess negative symptoms carefully. They recommend The Brief Negative Symptom Scale, which covers five core areas:
- Anhedonia (lack of pleasure)
- Asociality (lack of socializing)
- Avolition (lack of motivation and activity)
- Alogia (reduced speech)
- 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 causes more subjective distress, so the patient is more likely to complain of it, while the family is more likely to notice negative symptoms. Patients may complain of the effect of negative symptoms, such as not reaching their life goals.
If due to depression, 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.
For persistent primary negative symptoms, options include
- Add-on antidepressant treatment even without depression
- Modafinil (or armodafinil, which has steadier levels throughout the day)
- Transcranial magnetic stimulation
Those were all conditional recommendations based on modest evidence. Avoid THC (cannabis), which worsens negative symptoms. Dietary supplements, oxytocin, anti-inflammatory agents, oxytocin, naltrexone, and NMDA-targeting agents (eg, memantine) are not recommended due to weak evidence.
Cognitive remediation, social skills training, CBT for psychosis, and exercise are also recommended add-ons.
Dr. Aiken’s Note
Nearly all the medications and CAM therapies for negative symptoms have small effect sizes and weak evidence, so its somewhat arbitrary to recommend modafinil, and TMS over the rest. Another approach is to personalize them based on comorbidities they address.
Among supplements, ginkgo and sarcosine have the best evidence for negative symptoms. Other supplements and medications are supported by a few randomized trials for negative symptoms and have more robust evidence for common comorbidities.
- Tardive dyskinesia or vascular disease: Ginkgo (egb 761)
- Low energy or sleep apnea… Modafinil
- High cholesterol… Omega-3
- Obesity or irritable bowel syndrome… Probiotics
- Folate deficiency, MTHFR abnormality, or inflammation…. l-Methylfolate
- Arthritis… Curcumin or NSAID
- Menopausal women, and women with osteopenia: Raloxifene (estrogen receptor modulator)
- Acne… Minocycline
- OCD… Lamotrigine, topiramate, or memantine (all may help negative symptoms)
- Hypertension, insomnia, irritability… Clonidine or guanfacine
- Significantly low testosterone or vitamin D… Treat that
- Meth or cocaine use… Citicoline
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
