man holding stomach

Schizophrenia is a serious mental health disorder that can significantly disrupt the lives of individuals and families, which makes seeking effective, evidence-based schizophrenia treatment essential for anyone who receives a schizophrenia diagnosis.

The World Health Organization (WHO) reports the following prevalence data for schizophrenia.

Schizophrenia Worldwide

  • About 20 million people meet clinical criteria for schizophrenia
  • That’s roughly 1 in every 300 people, or 0.32%
  • Among adults 18+, the rate is slightly higher: 1 in every 222 people, or 0.45%

The National Institute of Mental Health (NIMH) reports the following prevalence data for schizophrenia in the U.S.

Schizophrenia in the United States

  • About 1.5 million people meet clinical criteria for schizophrenia each year
  • The lifetime prevalence – meaning the percentage of people who meet criteria for a clinical diagnosis at any point in their lives – falls between 0.25% and 0.64%

The symptoms of schizophrenia – which we’ll discuss in detail below – can make it difficult for individuals to engage in the basic activities of everyday life. Schizophrenia symptoms can cause problems in relationships, work, and school. That’s why evidence-based schizophrenia treatment is necessary. Without treatment, many individuals with schizophrenia have a difficult time living a full and fulfilling life. However, according to the NIMH, with evidence-based schizophrenia treatment, many individual with schizophrenia can “engage in school or work, achieve independence, and enjoy personal relationships.”

Treatment-Resistant Schizophrenia

While many people with schizophrenia experience positive outcomes with schizophrenia treatment, there’s a subset of people diagnosed with schizophrenia – about 34 percent – who don’t respond to schizophrenia treatment. Individuals diagnosed with schizophrenia who do not experience symptom improvement after two of more trials of antipsychotic medication – with proper adherence and appropriate dosage – meet the criteria for treatment-resistant schizophrenia (TRS).

Given the significant disruption caused in the lives of people with schizophrenia, two recent studies on schizophrenia may lead to a new understanding of the disorder. The publications “Involvement of Gut Microbiota in Schizophrenia and Treatment Resistance to Antipsychotics” and “The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment” explore the relationship between the gut microbiome – which we’ll also discuss below – and treatment-resistant schizophrenia (TRS).

Before we explore the results of those studies and discuss their implications for schizophrenia treatment, we’ll back up and ensure we’re all on the same page. First, we’ll offer a basic definition of schizophrenia. Then we’ll discuss the known causes of schizophrenia, list the most common symptoms,  and discuss the consequences of untreated schizophrenia.

What is Schizophrenia?

According to the National Institute of Mental Health (NIMH), schizophrenia is a severe mental disorder that affects people’s thinking, mood, social functioning, perception of their surroundings, and sense of personal safety. It’s important to recognize the symptoms of schizophrenia and seek treatment as early as possible. Untreated schizophrenia rarely, if ever, resolves without professional treatment and support.

Here’s the official definition published by the NIMH:

“Schizophrenia is a mental disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions. Although the course of schizophrenia varies among individuals, schizophrenia is typically persistent and can be both severe and disabling.”

That’s what schizophrenia is.

Now let’s look at what we know about the causes of schizophrenia.

What Causes Schizophrenia?

Research scientists have not identified exactly what causes schizophrenia. Our current understanding indicates that a combination of genetics, brain structure and function, and environmental factors contribute to the development of the disorder. The known risk factors for schizophrenia include:

  • Family history of schizophrenia. This is the genetic component of schizophrenia risk.
  • Birth complications that can affect brain development. This is the brain structure and function component of schizophrenia risk.
  • Living in poverty, living in stressful or dangerous surroundings, and exposure to harmful chemical or substances of misuse. These are the environmental components of schizophrenia risk.

With regards to what causes treatment-resistant schizophrenia, research suggests the following:

  • Neurotransmitter pathology:
    • Dopamine supersensitivity
    • Hyperdopaminergic and normodopaminergic subtypes
    • Glutamate dysregulation
    • Serotonin dysregulation
  • Inflammation
  • Oxidative stress, i.e. the inability of some cells in the brain and body to process toxins that can cause cell and tissue damage

However, none of those phenomena accurately predict the development of TRS. That’s why the studies on the impact of the gut microbiome on TRS are relevant: they seek to answer and as-yet unanswered question in our collective knowledge of schizophrenia.

Next, let’s look at the symptoms of schizophrenia. Although the number of people with schizophrenia is small, compared to disorders like depression or anxiety, schizophrenia is one of the top causes of disability in the U.S. and world. That’s why understanding the symptoms – i.e. what schizophrenia looks like in reality in an real person – is important. The earlier we can recognize schizophrenia or TRS in an individual, the sooner we can help them learn to manage their symptoms.

Signs and Symptoms of Schizophrenia

The onset of schizophrenia is usually gradual, starting with changes in behavior and mood. To friends and family members, the early symptoms of schizophrenia may be easy to miss, and the onset of more severe episodes may seem sudden and unexpected. Symptoms vary from person to person, but a diagnosis will typically identify three main categories: psychotic, negative, and cognitive. Evidence shows the average age of onset, i.e. when the symptoms of schizophrenia first appear, occurs between ages 14 and 30.

However, in many cases, diagnosis may lag behind symptom onset for months or even years. That’s another reason understanding everything we can about schizophrenia matters: people who receive a diagnosis have often experienced the symptoms of schizophrenia for a long period of time, which can exacerbate the severity of the disorder and its symptoms.

Experts divide the symptoms of schizophrenia into two categories: psychotic symptoms and negative symptoms.

We’ll discuss those now, stating with psychotic symptoms.

Psychotic Symptoms

The NIMH indicates that the term psychosis refers to any condition that distorts or impairs an individual’s contact with or understanding of reality. People with psychotic symptoms often experience the world in a way that’s disconnected from what’s actually happening in the world. In the diagnosis of schizophrenia, psychotic symptoms are often labeled positive symptoms, to differentiate them from the negative symptoms of schizophrenia that may be present in other disorders, or among people without a mental health disorder.

Common psychotic symptoms associate with schizophrenia include:

  • Hallucinations: Physically experiencing something that is not there. Hallucinations may be seen, heard, smelled, tasted, or felt. Hearing voices is especially common in those who suffer from schizophrenia. They may experience these hallucinations for some time before anyone in their life notices a problem.
  • Delusions: While hallucinations are imagined physical experiences, delusions are beliefs that are not true and seem irrational to others. An example would be the belief that those in their life are trying to cause them harm or the belief that their medication is designed to control them instead of helping them.
  • Thought disorder: This term describes symptoms of unusual, illogical, and hard-to-understand thoughts. Individuals may have trouble organizing their ideas and expressing them to others. They may also stop talking in the middle of a thought, jump from topic to topic with little or no logical transition, or simply make up words that have no meaning.
  • Movement disorder: This is when a person moves abnormally. For example, a person with schizophrenic may repeat specific motions over and over.

Negative Symptoms

Negative symptoms include things like loss of motivation, withdrawal from social life, difficulty expressing emotions, and difficulties with functioning. Some of these may be mistaken as symptoms of depression. However, while depression may manifest similarly, there are some distinct differences. Some examples of negative symptoms include.

  • Difficulty anticipating and feeling pleasure in everyday activities
  • Limited facial expressions and adopting a dull or monotonous manner of speech
  • Isolating oneself or having difficulty with socialization
  • Difficulty planning and executing everyday activities

Cognitive Symptoms

Cognitive functioning refers to a variety of mental processes, such as thinking, reasoning, remembering, problem-solving, decision-making, and learning. In some cases, someone with schizophrenia may find that they suffer from interruptions to these processes resulting in a significant impact on their day-to-day functioning. Some of the symptoms described also overlap with attention-deficit/hyperactivity disorder (ADHD) and other learning disorders, and so these symptoms may be mistaken or overlooked.

Cognitive symptoms may include, but are not limited to:

  • Difficulty following conversations
  • Difficulty learning new things
  • Difficulty processing information
  • Inability to use new information after learning it
  • Difficulty paying attention
  • Inability to remember appointments

These symptoms vary in severity over time, with periods of worsening and/or remission of symptoms.

Potential Effects of Untreated Schizophrenia

Untreated schizophrenia can cause extreme disruption, frustration, and complications in the life of a person with schizophrenia and the lives of their friends and loved ones. The disorder can be completely debilitating. Without treatment, people with schizophrenia may experience the following negative consequences:

  • Strained relationships with family and friends
  • Suicide, suicide attempts, and suicidal ideation
  • Co-occurring mental health disorders such as anxiety and depression
  • Misuse of alcohol and/or substances
  • Impaired ability to work or attend school
  • Financial problems
  • Homelessness
  • Social isolation
  • Health and medical problems
  • Being victimized
  • Aggression

These negative consequences are the reason a person with schizophrenia needs professional help and support. They’re also the reason we need to understand the data from the two studies we introduce in the beginning of this article, which seek to answer the question we pose in the title:

Can an unhealthy gut lead to treatment-resistant schizophrenia?

Let’s take a look at what they found.

The Gut Microbiome and TRS: What’s the Connection?

The gut microbiome refers to the totality of the various species of bacteria that live in our digestive system. Experts indicate that in each gram of bowel content (yuck) of our large intestine and small intestine, there are between one hundred billion and one hundred trillion bacterial cells. Collectively, those bacterial cells constitute the gut biome.

Our gut biome helps keeps us healthy in various ways. When the bacterial balance in our gut microbiome is disrupted, we experience something called gut dysbiosis. Experts indicate gut dysbiosis may play a role in the following mental health disorders and/or conditions:

The studies we examine in this article are the first to examine the relationship of the gut microbiome and treatment-resistant schizophrenia (TRS).

The first one – “Involvement of Gut Microbiota in Schizophrenia and Treatment Resistance to Antipsychotics” – involved establishing a connection between TRS and the gut microbiome. The second, “The Gut Microbiome in Schizophrenia and the Potential Benefits of Prebiotic and Probiotic Treatment,” examined schizophrenia treatment related to the gut microbiome.

We’ll start with the first one.

Gut Bacteria and Schizophrenia: Are Specific Species Related to Treatment Resistance?

In this study, researchers analyzed the results of 38 patients with schizophrenia. Among this set of participants, the 20 patients who responded to typical treatment with antipsychotic medication were labeled the SCZ-R group, and the 18 who did not were labeled the TRS (treatment-resistant) group. Researchers identified the contents of the gut microbiome of both groups in order to discern whether those with TRS differed from those who responded to treatment, and compared results from both groups to a set of 20 individuals with no schizophrenia diagnosis. Researchers labeled this past group of participants the HC (healthy control) group.

Here’s what they found.

The Gut Microbiome, Schizophrenia, and Treatment-Resistant Schizophrenia

  • A specific gut microbiome composition was present in SCZ-R and TRS groups that was not present in the HC group
  • Specific bacterial species were present in TRS group, but not in the SCZ-R or HC groups
  • Specific bacterial species were present in SCZ-R group, but not in the TRS or HC groups

We’ll stop here for a moment. What those results show is that people with TRS and SCZ-R had distinct microbiome profiles that different than those in the HC group, people in the TRS group had distinct and separate profiles than those in the SCZ-R group, and that people in the SCZ-R group had microbiome profiles that were different than those in the TRS and HC groups. That’s a preliminary indication that the gut microbiome may play a separate and distinct role in both schizophrenia and treatment-resistant schizophrenia.

Now let’s look at how these groups responded to treatment with antipsychotic medication.

The Gut Microbiome, Schizophrenia, and Treatment-Resistant Schizophrenia: Response to Medication

  • Patients in the TRS group showed a specific and distinct gut microbiome signature, different than the SCZ-R group and the HC group
  • Patients in the SCZ-R group showed a specific and distinct gut microbiome signature, different than the TRS group and the HC group
  • Patients in the HC group lacked one specific species of bacteria that was present in both the SCZ-R group and the TRS group.

This data tells us that the TRS group and SCZ-R group had specific and distinct microbiome signatures that predicted either a positive response to medication, or an absence of response to medication. That’s preliminary evidence for the role of the gut microbiome in response to antipsychotic medication for people with schizophrenia. In other words, we have the beginning of an answer to the question we pose in the title of this article:

While evidence does not prove an unhealthy gut leads to TRS, researchers have identified specific microbiome signatures common to people with TRS, people with schizophrenia that is not treatment resistant, and people without a diagnosis of schizophrenia.

Now let’s look at the second study.

Can Treatment With Prebiotics or Probiotics Help Treatment Resistant Schizophrenia?

With the role of the gut microbiome established in previous research – like the study above – researchers in the next study explored whether treatments that directly affect the contents of the gut microbiome had an impact on the symptoms of schizophrenia.

We’ve all heard of probiotics: they’re present in food like yogurt, kefir, kombucha, and other foods that involve a fermentation process. A probiotic is defined as a bacterial species that survives in the human digestive system and has a proven health benefit for humans. A prebiotic, on the other hand, is a specific type of dietary fiber that promotes the growth of probiotics.

In this meta-analysis, researchers examined the use of prebiotics and probiotics – a therapeutic class of treatment called psychobiotics – in three studies on patients with TRS.

Here’s what they found.

First Study:

  • Researchers observed an absence of gastrointestinal distress common to treatment with antipsychotics
  • Patients with the presence of one specific bacterial species – Candida albicans – did not respond to treatment, while patients with Candida albicans present responded to treatment

Second Study:

  • Patients with various mental health disorders received treatment with the probiotic Bifidobacterium breve A-1
  • These patients showed reduction in:
    • Psychotic symptoms as measure by the Positive and Negative Syndrome Scale (PANSS)
    • Depressive symptoms
    • Anxiety symptoms

Third Study:

  • Clinicians treated patients with schizophrenia with a combination of vitamin D and the probiotics Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus fermentum, and Lactobacillus reuteri
  • Clinicians reported significant decreases in:
    • Overall PANSS scores
    • PANNS scores on positive symptoms of psychosis
    • PANNS scores on negative symptoms of psychosis

While the results of this last study are promising, the study design did not allow researchers to determine whether improvements in PANNS scores were the result of vitamin D, probiotics, or a combination of the two.

How This Research Helps

Many biomedical research experts refer to work on the gut microbiome as the final frontier or a bold new frontier in health research. Experts in mental health treatment refer to the gut-brain axis, and point to research that shows the gut microbiome plays a role in regulating stress response, immune function, and neurotransmitter function.

When research identifies specific gut microbiome profiles that correspond to specific pathologies or diseases – including mental health disorders – that implies, or at least raises the possibility, that medications that act directly on the gut microbiome may have an impact on those specific pathologies.

That’s where we are right now in this research, with regards to treatment-resistant schizophrenia: studies match gut microbiome profiles to cases of TRD, and match gut microbiome profiles with resistance to specific types of antipsychotic medication.

That’s a significant step – but it only takes us halfway to what we want: effective medications for TRS. The next step in research, in the words of the second study we examine above, is this:

“The use of prebiotics and probiotics to treat symptoms of SCZ and its comorbidities is promising, albeit it is still in its early stages. Larger scale studies with psychobiotic treatment at various stages of schizophrenia could help conclude the role of  the gut microbiome schizophrenia.”

That research is currently in progress. We’ll keep a close eye on the medical journals, and when more studies appear on this subject, we’ll report on them here. In the meantime, the takeaway here is positive: we’re learning more about TRS – and how to treat it – every day.