Negative Symptoms in Schizophrenia: An unmet need

Psychiatric diagnosis is often an artful combination of science and intuition. As a psychiatric resident, I had only seen a handful of patients with a schizophrenia diagnosis, and therefore my intuition for what ‘negative symptoms’ are, was largely bookish—meaning, I had read about them but hadn’t been expose to enough patients in order to build an intuition. Several years following residency, I had the privilege to interact with a patient who taught me about them and helped me develop that much needed intuition.

“Jack” was a delightful individual to meet. Very polite and mild-mannered. He was brought in by his parents who were concerned for his safety and functional decline. He had been spending too much him in his basement doing very little, occasionally listening to music (a combination of death metal and hard rock). He had been obsessing on religious scripture and its interpretation per their report, but when I asked him about that he kept saying that they are blowing things out of proportion. What scared them the most is that at one point he had made a gesture indicating that he was going to injure himself, but didn’t act on it in any way. The clinical interview did not reveal any evidence for positive symptoms; meaning he denied that one piece of data on religious preoccupation and also scoffed at questions related to auditory hallucination and all types of delusional thinking. He had been seen by one other psychiatric provider who had prescribed him an SSRI for anxiety.

This meeting was perplexing because he gave a very convincing story of everything being just fine. His cognitive exam was also quite remarkable—no issues with his attention or working memory. The only ‘soft’ sign that I was able to hang my hat on was his spontaneity—he did not initiate conversation at all. He only responded when spoken to, even when I deliberately stayed silent for minutes. This is something that is actually hard for people to do, sit in an interview for several minutes in silence. But that was not all, his functional decline evident by him dropping out of college a year ago, not being able to keep a job in the interim and recently ending a romantic relationship were other signs that were supportive of a schizophrenia diagnosis (if conditioned on the putative avolition being a negative symptom).

Therefore, I formulated the hypothesis that this is schizophrenia (confidence level was quite low, but the risk of simply doing nothing was high), so I asked if he would be willing to try a low dose anipsychotic. We talked about the risk and benefits for a while and he agreed to a very low dose of risperidone. Within a couple of days, I had a tentative answer—he became more spontaneous in his interactions with me. Trying to temper my diagnostic validation and playing devil’s advocate, I decided to speak with his family a few days later. Only when his parents said, “We got our son back,” did I feel confident in the diagnosis.

I am grateful that Jack and I met because since then, I had been able to diagnose negative symptoms much more readily—My experience with him underscored the complexity of diagnosing schizophrenia on the basis of negative symptoms alone. In speaking with colleagues in the field, I think this sentiment is common.

A little on negative symptoms

Negative symptoms are deficits in emotional and social functioning. Unlike positive symptoms—such as hallucinations or delusions—which represent an excess of normal functions, negative symptoms are characterized by a lack of typical abilities. They include:

• Affective flattening: Diminished emotional expression.

• Avolition: Reduced motivation to initiate and sustain goal-directed activities.

• Anhedonia: Inability to experience pleasure.

• Alogia: Poverty of speech or thought.

• Asociality: Reduced interest in social interactions.

In the case of Jack, avolition was the most prominent feature. He displayed little initiative but responded when prompted, and was quite pleasant. This passivity can easily be misattributed to depression or personality factors, but in the context of the entire clinical picture (including functional decline), negative symptoms of schizophrenia are a key differential diagnosis. Interestingly, network analysis of symptom clusters has indicated that avolition is central to negative symptoms and can track treatment efficacy quite well.

Negative symptoms can have devastating consequences on individuals and their families. These symptoms impair one’s ability to engage in meaningful relationships, pursue education or work, and live independently. While positive symptoms may attract more clinical attention due to their acute nature, negative symptoms often persist even when positive symptoms remit, leading to long-term disability. Families, like Jack’s, often describe the experience as a “loss” of the person they once knew.

Neurobiology of Negative Symptoms and emerging treatments

The neurobiological basis of negative symptoms is complex and not yet fully understood. Most of the current proposals are neurochemical, which fall along the well-known dopaminergic and glutamatergic hypotheses of schizophrenia more generally. Specifically:

• Dopaminergic dysfunction: Hypoactivity in the mesocortical dopamine pathway, which may underlie motivational deficits. This is in contrast to positive symptoms that are thought to be related to dopaminergic hyperfunction in mesolimbic pathways.

• Glutamatergic dysfunction: Impairments in NMDA receptor function, particularly in the prefrontal cortex.

There are some proposals that are circuitry-based, building on a relatively recent resting state functional connectivity finding, where the cerebellar connectivity with prefrontal cortex is a putative readout for negative symptoms in schizophrenia. This idea is quite intriguing, particularly given the preliminary evidence that TMS to the cerebellar vermis appears to improve negative symptoms in patients.

More generally, treating negative symptoms pharmacologically is challenging. Most traditional antipsychotics are effective for positive symptoms but have little impact on negative symptoms. However, several promising treatments are on the horizon:

• Muscarinic agonists (e.g., KarXT): KarXT’s novel mechanism, which targets muscarinic receptors rather than dopaminergic pathways, offers potential benefits for both positive and negative symptoms. Its distinct mode of action may also reduce the risk of common side effects associated with traditional antipsychotics.

• Glutamate modulators: Drugs that enhance NMDA receptor function are being explored to address the cognitive and motivational deficits linked to negative symptoms.

• Pro-cognitive agents: These aim to improve specific domains of cognition and motivation that are often impaired in schizophrenia. For example, guanfacine has some impact on negative symptoms particularly when coupled with cognitive behavioral therapy (CBT).

Challenges in Diagnosis

Returning to Jack, the initial diagnostic uncertainty reflects a broader issue in psychiatry: the absence of precise, objective biomarkers for negative symptoms. Rating scales like the PANSS (Positive and Negative Syndrome Scale) and BNSS (Brief Negative Symptom Scale) provide a framework for assessment but rely heavily on subjective reporting.

Advances in neuroimaging, digital phenotyping, and computational modeling hold promise for improving the precision of psychiatric diagnoses, potentially leading to earlier intervention and more targeted treatments.

Conclusion

The story of Jack illustrates both the challenges and the hope in treating negative symptoms of schizophrenia. His family’s heartfelt statement, “We got our son back,” speaks to the profound relief effective treatment can bring. Yet, for many patients, the road to recovery remains fraught with uncertainties. By pushing the boundaries of research and clinical care, we can strive to bring that same relief to countless others navigating the complexities of schizophrenia.