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Rocco Marotta, MD, PhD on Treatment Resistant Schizophrenia in Young Adulthood

Silver Hill Hospital

In early November 2023, Dr. Rocco Marotta, MD, PhD, Director of the Center for the Treatment and Study of Neuropsychiatric Disorders at Silver Hill Hospital presented at a collaborative continuing education event hosted by The Dorm, a leading young adult mental health treatment program (IOP) located in New York City.  The topic was Treatment Resistant Schizophrenia in Young Adulthood. The article following captures the thoughts in information expressed in that presentation. 

Dr. Marotta (at right with colleagues) has several decades of experience working with clients experiencing schizophrenia. In this presentation he outlines several medication options and the “5 pillars of care” that he recommends for long-term recovery and symptom reduction, giving hope to impacted individuals, their families, and their communities.

A video of the presentation may be viewed here

Primer: What is Schizophrenia?

Schizophrenia is a developmental disorder and brain disease most notably characterized by hallucinations, delusions, and paranoia. While mental healthcare providers have come a long way in helping alleviate debilitating symptoms through treatment and medication, over one third of clients continue to have symptoms despite multiple trials of antipsychotic medications. This is known as treatment resistant schizophrenia.

Dr. Marotta explains that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines schizophrenia as a chronic mental illness with positive symptoms, negative symptoms, and cognitive impairment.

Positive symptoms are defined as symptoms that are present in individuals with psychosis and can include:

  • Hallucinations (hearing voices or seeing things that do not exist)
  • Delusions and paranoia
  • Distorted or exaggerated perceptions, beliefs, and behaviors

Negative symptoms are defined as thoughts and behaviors that are absent in individuals with psychosis and can include:

  • Lack of motivation
  • Lack of a desire to seek social connection
  • Decrease in the ability to initiate plans and express emotion

Cognitive impairments are changes in the brain structure that result in decreased quality of life. Some examples of cognitive impairment include:

  • Deficits in attainment of life goals
  • Deficits in educational attainment
  • Deficits in IQ

Dr. Marotta explains that clinicians often try to treat the positive (overt) symptoms first, which is the main focus of antipsychotic medication. However, “The bread and butter of it [treatment], and of saving lives, and families, and societies, is not just getting rid of the overt symptoms, but doing something about the withdrawn, negative, symptoms and also to be able to impact and improve cognition,” he says.

Schizophrenia is not the only cause of psychotic symptoms in young adults. Psychosis can also be induced by brain damage, epilepsy, drug use, or other health conditions. Additionally, other mental health disorders may also involve psychosis, including bipolar disorder, severe depression, and postpartum psychosis.

Dr. Marotta outlines a spectrum of disorders that can present with psychosis, including:

He notes that because clinicians and neurobiologists don’t yet completely understand the biology of schizophrenia, and it actually may be an umbrella diagnosis for several overlapping disorders, adding to the complexity of designing effective treatment plans.

Rising Rates of Psychosis in the United States

Dr. Marotta observes a rising rate of psychosis in his young adult clientele, a clinical observation backed by several concerning statistics. He notes that:

From his experience Dr. Marotta believes that the increased rate of youth smoking cannabis at a much younger age may be the cause of the rising rates of psychosis in the U.S. “The real kicker is whether or not a substance-induced psychotic state will evolve into schizophrenia,” he notes. “It’s my belief that that is what’s happening.”

What Makes Schizophrenia so Resistant to Treatment?

Approximately one percent of the population is diagnosed with schizophrenia, and almost 40% of those entering treatment who have received multiple trials of antipsychotics do not recover sufficiently. This presents an enormous burden onto individuals, their community and society. So what makes schizophrenia so resistant to treatment?

Dr. Marotta outlines the following factors that contribute to treatment resistance:

  • A lack of societal mechanisms or structures in place to support people who have schizophrenia
  • A lack of social support for people who have schizophrenia
  • Ongoing sociocultural and environmental stressors (for example, stress related to the aftermath of the COVID pandemic)
  • High rates of substance use
  • Lack of scientific understanding about the underlying neurobiology of schizophrenia

On the flip side of these barriers are the “5 pillars of treatment” Dr. Marotta recommends finding long-term stability with schizophrenia.

The pillars of schizophrenia treatment

As a specialist in neuropsychology, Dr. Marotta has extensive experience and expertise in treating clients through medication. However, he emphasizes the importance of the five main pillars of schizophrenia treatment, which go beyond using medication alone:

  1. Medication Compliance
  2. Trust between the patient, their family, and their healthcare providers
  3. Sobriety
  4. Ability to sustain social contact
  5. Availability of lasting professional and family support

Even after initial treatment, maintaining these pillars are vital to helping an individual lessen their most debilitating symptoms and improve their daily functioning.

Medications for Schizophrenia Treatment

It is not possible to treat schizophrenia with medication alone, explains Dr. Marotta. However, medication can be very effective when paired with social support and a community framework. He goes on to provide an overview of the types of medication that are most commonly used with clients experiencing symptoms of schizophrenia:

Dopamine Blockers

The traditional medications for schizophrenia are dopamine blockers, as one of the theories about the presentation of schizophrenia is that it is caused by an excess of dopamine.


Clozapine is a powerful antipsychotic recommended for patients who have failed two adequate trials of other antipsychotics. It reduces aggression, irritability, and suicidality and it controls positive symptoms. Additionally, compared to other pharmacological options, it has a much higher rate of helping with negative symptoms, as well as possible improvement of cognitive abilities.

Clozapine is the most powerful antipsychotic medications available, with the best clearance rate, it is still important to note the potential side effects it may cause—the most serious of which is that one in 100 patients will develop a granulocytosis, which means that they could die of an infection. Because of this high rate, patients must have blood tests every week for the first six months, then every other week, and then every month, which can be a challenging commitment. For this reason it’s one of the lesser-used medications used in treatment.

Clozapine with Sublingual Oxytocin

What makes clozapine most useful is its ability to address continuing negative symptoms, but a significant number of patients still have deficits with negative symptoms and cognitive functioning. To find more helpful interventions, other medications including anti-depressants and stimulants have been supplemented in addition to clozapine, without a large effect. Dr. Marotta and his team have found great success for many of their patients using clozapine with sublingual oxytocin.

A note on Oxytocin’s role in the body

It is important to understand oxytocin’s role in the body, explains Dr. Marotta. Oxytocin is a nine-amino acid peptide already produced in the human body and neurotransmitter that assists with familial and non-familial bonding, sociosexual behaviors, appetite-related behaviors, cardiovascular and metabolic homeostasis, muscle and nerve regeneration, as well as pain relief, anti-inflammation, and wound healing, to name a few. These are all factors that may be hindered by schizophrenia.

Sublingual Administration

Another important thing to consider is how this oxytocin is administered. Dr. Marotta and his team decided on sublingual delivery, which involves placing the medication under the tongue, for it to dissolve and be absorbed into the bloodstream through the tissue there. Sublingual delivery was chosen to avoid triggering behaviors used by substance users, as well as for its relatively cheaper cost compared to intranasal preparations.

Dr. Marotta explains that the benefits of their treatment protocol include the repairment of psychotic symptoms and mood regulation through clozapine, the impact of interpersonal relatedness and motivation through oxytocin, as well as regenerative processes facilitated by all factors of schizophrenia treatment: clozapine, oxytocin, sobriety, and reinforcement of social interaction.

Treatment Resistant Schizophrenia: Establishing Ongoing Support for Symptom Reduction

Dr. Marotta’s treatment team has helped many clients and their families find stability, and he attributes this to his innovative medication protocol and their emphasis on a multi-pronged approach to treatment. Many of his past patients, he notes, have gone on to lead fulfilling lives, attend graduate school, and hold long-term relationships.

He underscores the importance of other forms of treatment in order to find stability with schizophrenia, including:

  • Individual therapy, especially cognitive behavioral therapy
  • Group therapy
  • Societal support
  • Spiritual support

He cites support groups like Alcoholics Anonymous as a resource that has been helpful for many of his patients because of its community element and emphasis on sustained sobriety. “AA is a powerful tool, as far as I’m concerned, for many of our patients,” he says. “I look at that as a form of spiritual intervention.”

Moving forward for treatment development for schizophrenia, Dr. Marotta calls for more societal structures in place for patients, including normalizing sober living, promoting social connectedness, establishing better family therapy support options in the society at large.  “For families to support their loved ones, they need support from their community,” he says.

In conclusion, though the phrase “treatment-resistant” may imply that a condition cannot be easily treated, research is constantly evolving and improving methods of treatment that are effective against these “treatment-resistant” disorders. For schizophrenia, it is very possible to decrease the harshest symptoms and become fully functioning through medications, therapies, and familial and social support.

To learn more, watch the entire presentation here, which concludes with a valuable audience Q+A segment.