Treatment-Resistant Schizophrenia: Can DBS Be the Solution?

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TALES FROM THE CLINIC

-Series Editor Nidal Moukaddam, MD, PhD

In this installment of Tales From the Clinic: The Art of Psychiatry, we explore deep brain stimulation (DBS) for psychotic symptoms. Despite advances in psychotropic agents, treatment-resistant psychotic symptoms remain surprisingly prevalent in schizophrenia spectrum disorders. DBS could be an attractive option in terms of effectiveness, though more studies are needed. As with all psycho-surgery intervention choices, DBS is underutilized and ethical issues—as well as knowledge, cost, and acceptability issues—represent barriers to usability.

Case Vignette

“Delilah” is a 35-year-old woman who was diagnosed with schizophrenia 8 years earlier. She first presented to the emergency department (ED) when she was brought from the airport, where she was trying to get through security without a ticket. Delilah reported paranoia, persecutory delusions that the FBI was spying on her through air-conditioning vents, and command auditory hallucinations to run to the top of the mountains so she could see those following her. These symptoms severely affected Delilah’s functioning, eventually forcing her to resign from her elementary school teaching job as she continually accused colleagues and parents of working for the FBI and conspiring against her. She severed all her family ties as she would not allow anyone near her or check on her, which lead to increased isolation.

In the 3 years following her initial presentation, Delilah had numerous hospitalizations where antipsychotics (first and second generation) were tried either as single agents or in combination, sometimes above the usual US Food and Drug Administration (FDA) recommended maximum dose, but with continued treatment failure. She would report a decrease in frequency of hallucinations at the end of hospitalizations but symptoms promptly relapsed. She was discharged on a long-acting injectable agent more than once, but refused to follow up for further dosing. Her behavior was escalating: in 1 incident, during an episode of psychosis, she climbed the roof of her apartment-complex and started cutting the air-conditioning ducts. The apartment manager called the police and as the officers approached her, she tried to defend herself with a hammer, leading to her arrest. She was sent to a state hospital for capacity restoration. There, she was started on clozapine with good results in controlling her behavior and decreasing her level of disorganization and delusions. However, 1 year shy of starting on clozapine, she developed severe neutropenia and clozapine had to be stopped. She was restarted on combinations of other agents with poor results even when combined with electroconvulsive therapy (ECT). A rechallenge with clozapine was attempted but she developed the neutropenia again this time 2 months into the treatment, so it was discontinued.

During the second clozapine treatment and as the treating team was suspicious of the possibility of having to stop clozapine and the possibility of severe decompensation, Delilah was offered to participate in a clinical trial of deep brain stimulation (DBS) and she agreed. Her capacity to consent for treatment was assessed by her treating team, the researchers, and an independent psychiatrist, which satisfied the trial’s independent review board. A few weeks after the DBS leads placement and due to the reemergence of symptoms after stopping clozapine, the system was activated. Within 2 weeks of adjustments, Delilah reported marked resolution of symptoms. Temporary discontinuation of stimulation or decreasing the amplitude, unknown to the patient, was associated with immediate return of hallucinations. After 24 weeks, she was deemed fit for outpatient treatment and 1 year into treatment she continues to function with minimum supervision and acceptable outpatient follow up frequency.

Discussion

DBS is a neurosurgical procedure that has been increasingly recognized as a potential treatment for various neurological and psychiatric disorders, including schizophrenia.¹ DBS involves the delivery of electrical pulses to specific brain regions via surgically implanted electrodes, aiming to modulate neural circuits and alleviate symptoms.²

The concept of DBS dates back to the early 20th century, but it was not until the late 1980s that it became a viable treatment option for movement disorders such as Parkinson disease.³ Over the years, the application of DBS has expanded to include psychiatric conditions, including obsessive compulsive disorder (OCD) and major depressive disorder (MDD). The FDA approved the use of DBS for OCD in 2009, marking a significant milestone in the field of neuropsychiatry.⁴

DBS works by delivering electrical stimulation to specific brain areas, modulating the activity of neural circuits involved in the targeted disorder. The precise mechanism of action is still under investigation, but it is believed to involve a combination of effects, including the inhibition of overactive neurons, the excitation of underactive ones, and the modulation of local and network-level neural activity.⁵

Figure 1. Comparing DBS Electrode Size to a Quarter and Pacemaker

The use of DBS in the treatment of schizophrenia is a relatively new area of research.² Early studies in depressive disorders have targeted various brain regions, including the ventral striatum/ventral capsule, the subgenual cingulate, and the medial forebrain bundle, with mixed results. Some patients have shown significant improvements in symptoms, while others have shown minimal or no response.⁶ Patients with OCD treated with DBS could show improvement in accompanying depression.⁷ PET scan studies showed depressed mood was associated with increased resting activity in parts of the inferior medial frontal cortex and orbitofrontal cortex, leading to trials of DBS in treatment-resistant MDD using electrode placements in the subgenual anterior cingulate cortex. Knowing exactly where to place DBS electrodes in the brain for treatment of schizophrenia is difficult given the positive and negative symptoms of the disease (Figures 1 and 2).

Figure 2. DBS Electrode and Battery/Pacemaker Placement

Some clinical trials have been conducted to evaluate the efficacy of DBS in treating schizophrenia but the literature is still limited.⁸ Corripio et al aimed to examine the effectiveness of stimulating the nucleus accumbens and the subgenual anterior cingulate cortex (subgenual ACC) targeted DBS.² The primary outcome measure was PANSS total score. Of the 8 patients planned to receive treatment, 1 could not undergo treatment due to surgical complications. Of the 7 patients who received DBS, 5 (2 with NAcc and 3 with subgenual ACC electrode placements) met the symptomatic improvement criteria. The 5 patients who met the symptomatic improvement criteria showed a significant improvement in their symptoms, with a mean PANSS total score improvement of 58% for NAcc and 68% for subgenual ACC. Three of the 5 patients who met the symptomatic improvement criteria entered the crossover phase and all showed worsening of their symptoms when the stimulation was discontinued. The fourth patient who met the symptomatic improvement criteria worsened after the current was switched off accidentally without her or the investigators’ knowledge. Physical adverse events were uncommon, but 2 patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively).

Like any surgical procedure, DBS in psychiatric disorders carries potential risks, including infection, hemorrhage, and complications related to the device implantation and stimulation.⁹ In one study comparing morbidity and mortality in the use of DBS for treatment of Parkinson disease versus the morbidity and mortality risk of DBS implantation surgery in patients for treatment of schizophrenia and schizoaffective disorder, it was found that although risks of morbidity and mortality were lower in patients being treated for schizophrenia and schizoaffective disorder than Parkinson disease, there were still post surgical complications in this cohort.¹ Although infections and hemorrhages were less common in the schizophrenia and schizoaffective disorder group than in the Parkinson disease group, the schizophrenia and schizoaffective disorder group experienced higher rates of postsurgical morbidity, even after matching for presurgical factors.

Moreover, DBS can cause neuropsychiatric adverse effects, such as mood changes (mania and hypomania, sometimes depending on the device setting), cognitive disturbances (mild forgetfulness), and panic attacks related to stimulation. Other major barriers for increased use of DBS in treatment-resistant psychiatric disorders is historical baggage of psychosurgery.¹⁰ Therefore, careful patient selection and thorough preoperative assessment are crucial. Currently, DBS is considered for patients with severe, treatment-resistant schizophrenia who have failed to respond to conventional therapies.⁴

Ethical & Historical Considerations

The history of surgery in psychiatric medicine is a long and controversial one. In the early 20th century, lobotomy was a popular treatment for severe mental illnesses such as schizophrenia and depression. The procedure involved severing the connections between the frontal lobes and the rest of the brain, which was thought to calm the patient and make them more manageable. However, lobotomies often had devastating adverse effects, such as personality changes, memory loss, and even death.

The ethical dilemmas of DBS and lobotomy are similar in some respects. Both procedures involve altering the brain in order to treat mental illness, and both have the potential for serious adverse effects. However, DBS is a more targeted procedure, and the risks are generally lower than those of lobotomy. Additionally, DBS is typically used as a last resort for patients who have not responded to other treatments, while lobotomy was often used on patients who were considered to be a danger to themselves or others.

Ultimately, the decision of whether or not to undergo DBS is a complex one that should be made on a case-by-case basis. Patients and their families should carefully weigh the risks and benefits of each procedure before making a decision. Studies are underway to assess the capacity of individuals with schizophrenia to provide full informed consent and how the disease process itself affects executive functioning pertinent to the consent, or generates delusional material that would prevent consent to a potentially curative procedure.

In addition to the ethical dilemmas of DBS and lobotomy, there are also a number of historical factors that make these procedures controversial. Lobotomies were first performed in the 1930s, at a time when there was a lack of understanding of mental illness. Doctors were desperate for treatments that could help their patients, and they were willing to try experimental procedures with unknown risks. Lobotomies were also popularized by the media, which often portrayed them as a miracle cure for mental illness. As a result, many patients who underwent lobotomies did not fully understand the risks of the procedure, and they were not given informed consent.

Unlike lobotomies however, DBS is a completely reversible procedure. Even without removing the device from a patient’s brain, reversal of treatment/cessation of treatment is as easy as turning it off.

The history of lobotomy is a reminder of the importance of ethical standards in medicine. Patients should always be given informed consent before undergoing any medical procedure, and they should be fully aware of the risks and benefits of the procedure. Doctors should also be careful not to promote experimental procedures as miracle cures.

The informed consent issue is a barrier to using DBS in the treatment of treatment-resistant schizophrenia. In order to ensure that patients are giving truly informed consent, it is important to have a thorough discussion with them about the risks and benefits of DBS. Additionally, it is important to get the consent of a patient's surrogate decision-maker, if the patient is unable to give consent themselves.

There is no easy solution to the informed consent dilemma for patients with schizophrenia. However, by carefully discussing the risks and benefits of DBS with patients and their surrogate decision-makers, we can help to ensure that patients are making informed decisions about their treatment.

Another question is whether patients with schizophrenia can give informed consent for any treatment at all. Based on disease severity and how uncontrolled the disease is, these patients may not have the ability to give informed consent. In Calcedo-Barba et al, the authors deemed that there was no gold standard test to assess whether patients with schizophrenia can give informed consent or not.¹¹ Decision making ability must be assessed using clinical presentation and standardized tools. The authors also found that while some patients with schizophrenia are able to give informed consent as well as unaffected individuals, some patients may have impaired decision making. Patients with schizophrenia may have delusions or hallucinations that make them believe that DBS is not in their best interest. Even if it is possible to obtain consent, there is the issue of selecting patients for treatments with cases of schizophrenia severe enough to make DBS their last chance for treatment that will still benefit from treatment. Patients with treatment-resistance already have an inherently worse prognosis, so it is difficult to assess the efficacy of DBS in treating schizophrenia when it is only being used to treat the most desperate cases.

As a result, there is a risk that patients with schizophrenia may not be able to give truly informed consent to DBS. This is a serious ethical dilemma, as it could lead to patients undergoing a procedure that they do not fully understand or that is not in their best interest.

Cost

DBS is a costly procedure, with the initial implantation surgery typically costing around $100,000. The cost of the DBS device itself can range from $25,000 to $50,000, and the cost of follow-up programming and adjustments can be several thousand dollars per year. As a result, DBS is not accessible to everyone who could benefit from it.

There are a number of issues that patients face when trying to pay for DBS. In the United States, DBS is not covered by Medicare or most private insurance plans. This means that patients must pay for the procedure out of pocket, or they may be able to get financial assistance from a charitable organization. However, even with financial assistance, DBS can be a major financial burden for patients and their families.

The high cost of DBS and the difficulty of getting insurance coverage are major barriers to access for patients. As a result, many patients who could benefit from DBS are unable to afford it. In order to make DBS more accessible to patients, there needs to be more government funding for research and development.

Concluding Thoughts

DBS represents a promising, albeit challenging, frontier in the treatment of schizophrenia. While preliminary results are encouraging, further research is needed to refine the technique, identify optimal target regions, and establish clear guidelines for patient selection. As our understanding of the neural underpinnings of schizophrenia continues to evolve, so too will our ability to modulate these circuits and alleviate the suffering caused by this debilitating disorder.

Mr Shalaby is a third year medical student at the Texas A&M School of medicine interested in pursuing a career in psychiatry. He is passionate about psychiatric research relating to new and innovative treatments for psychiatric illnesses. Dr Shahin is assistant professor at Baylor College of Medicine, certified in general psychiatry & addiction psychiatry, and specializing clinically in the area of complex psychopharmacology management in the setting of cooccurring mental and physical disorders.

References

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