The University of Florida
Obsessive-Compulsive Disorder Program
Novel Non-Pharmacologic Treatments
While SRIs or CBT alone are often effective in the treatment of OCD, many patients have an inadequate or partial response. Although the majority of patients with OCD eventually show some improvement with conventional treatments (the best probably being a combination of an SRI and CBT), there is a sub-group of 5-10% of patients whose symptoms remain severe enough to call for less established approaches.
To be considered treatment-resistant, the OCD needs to have been unsuccessfully treated with pharmaceutical agents e.g. at least two SRIs. Treatment-resistant OCD is typically defined as having failed adequate trials of a selective SRI (SSRI), e.g., fluoxetine, a trial of the SRI clomipramine, and CBT. Adequate trials of an SSRI and clomipramine are defined as 10 to 12 weeks of continuous treatment at the maximally tolerated dose with no improvement of symptoms. An adequate trial of behavioral therapy is defined as a minimum of 20 to 30 hours of documented exposure with response prevention with no improvement. We estimate that up to 5% of the total population with OCD seeking care has severe, treatment-resistant illness. These patients, who experience tremendous suffering and functional impairment, have few treatment alternatives. New innovative approaches to treatment are needed for these severely ill patients.
Deep Brain Stimulation (DBS) involves putting a wire with tiny stimulating electrodes into your brain. The DBS stimulating device works like a heart pacemaker. The device will send out electrical impulses that will disrupt the natural electrical impulses given off by your brain cells. In order for your brain to send messages to your body, it produces a form of electricity. The signal being sent by DBS appears to interrupt this flow of electricity. The use of DBS in the treatment of OCD is investigational, which means it has not been approved by the Food and Drug Administration (FDA). DBS is approved by the FDA for use in people with uncontrollable shaking (essential tremors) and Parkinson’s disease (PD). There are two different DBS systems manufactured by Medtronic, Inc. and approved by the FDA. Unlike the other brain surgeries, DBS may not cause irreversible destruction of brain tissue. It also has the potential advantage of being adjustable after the procedure is completed. However, like some of the other neurosurgical approaches, this procedure involves creating holes in the scalp and skull and passing wires to locations deep within the brain.
The stimulation "target" is two small groups of nerve fibers deep in the brain called the anterior limb of the internal capsule. These fibers connect areas of the brain researchers believe are involved in causing the symptoms of OCD. Electrical stimulation of the internal capsule is a new approach that was first used in OCD in 1998.
Stereotactic Neurosurgical Procedures. Other options for the treatment of severely refractory OCD include stereotactic neurosurgical procedures. Stereotactic procedures are precise methods used to lesion or remove brain tissues utilizing a three-dimensional coordinate plane for location and identification. Some techniques employ radiation and others involve introducing electrodes that destroy brain tissue with heat. A number of patients with OCD have received these types of procedures over the years and there have been many reports of positive results. Even when the procedure fails to reduce the symptoms of OCD, adverse changes in personality or intelligence appear to be uncommon. This contrasts with the experience of procedures called lobotomies that were performed in the distant past, often with disastrous results, robbing the person of motivation and intellectual function. Although the modern techniques represent a vast improvement, targeting smaller areas more precisely, these procedures are all destructive (also called “ablative”); meaning, once the surgery is completed, the tissue that was destroyed cannot be restored.
Anterior Capsulotomy. Capsulotomy (CP) and cingulotomy (CG) are the most common neurosurgical procedures used to treat psychiatric illness. The capsulotomy has been used for three decades to treat refractory OCD, particularly when an individual’s illness is refractory to medication and/or behavioral treatments and causes profound interference with basic day-to-day functioning. A commonly employed surgical technique for capsulotomy is radio-frequency thermo-lesion. A radio-frequency thermo-lesion procedure is performed under local anesthesia and light sedation. The cerebral cortex contains no internal nerve endings for pain therefore a local anesthetic in the brain is not necessary. The stereotactic coordinates for the target area of the anterior limb of the internal capsule are determined with Magnetic Resonance Imaging (MRI). Small bilateral burr holes are made just behind the coronal suture, and monopolar electrodes of 1.5 mm are inserted into the target area. Thermo-lesions are produced by heating the non insulated tip of each electrode to approximately 75°C for 75 seconds creating a lesion approximately 4mm wide and 15-18 mm long.
A retrospective study, without modern rating scales but with strict response criteria, found 25 of 35 OCD patients were symptom-free or much improved an average of 35 months after CP surgery. Most (24 of 35) were unable to work preoperatively due to OCD, while 20 resumed work afterwards. A later prospective study using independent psychiatrists as raters found 16 of 35 patients were symptom free and 9 more much improved (70% response overall). A recent prospective study found that 8 of 15 patients had a 33% or more improvement in YBOCS severity. After open capsulotomy, transient adverse effects included postoperative headache, confusion, or incontinence. There were 2 intraoperative hemorrhages in a series of 50 open capsulotomies at the Karolinska, one without lasting consequences, but one associated with seizures. Persistent adverse effects, in a subset of 22 patients followed longitudinally at the same center, were memory complaints (17%), diminished attention to grooming (9%), fatigue (7%), and weight gain (an average increase of 10%). In another study, 7 of 26 patients with severe, refractory, non-OCD anxiety disorders had notable postoperative deficits, mainly apathy and executive dysfunction after open capsulotomy. The most recent study of open capsulotomy found 2 of 15 patients had transient complications (a single seizure in one patient and transient hallucinations in another). One of 15 had marked edema associated with a “progressive behavior disorder that became permanent” (no further details given).
Anterior Cingulotomy. In a CG, developed in the USA and Canada, electrodes are inserted in two adjacent targets in the cingulate bundle, a collection of fibers located between the hippocampus and the corpus collosum. After insertion the electrodes are heated to approximately 80-85º C for 100 seconds in order to form a lesion, surgeons tend to be very cautious with this procedure and sometimes the procedure needs to be repeated about 6 months later to elongate the lesion. Research in the 1950s compared CG and frontal lobotomy. Cingulotomy was as effective as lobotomy at alleviating patient suffering however it did not produce the same drastic changes in personality and increased violence. This is thought to be because with CG the primary structures of the frontal lobe, thought to house the personality, remain virtually undisturbed. Cingulotomy is effective with a relatively low occurrence of complications and late onset side effects. However, there was an instance of possible emotional shallowness, diminution of inhibition, elevation of mood, and loss of initiative similar to that in CP. Of the reviewed 32 cases of treatment-refractory OCD, approximately 30% of the patients reported a marked improvement after the procedure.
A retrospective study evaluated 33 OCD patients who underwent cingulotomy at Massachusetts General Hospital over a 25-year period. Using the YBOCS, the authors estimated that 25-30% of patients benefited substantially. A subsequent prospective study found that 5 out of 18 OCD patients were much or very much improved using conservative criteria, while 3 of 18 patients had lesser but still notable benefit (an improvement rate of 44% overall). The most recent prospective study by the same group studied 44 OCD patients with OCD using our proposed entry criteria. A mean of 32 months after one or more cingulotomies, 14 of 44 met conservative criteria for treatment response and 6 of 44 were partial responders, thus 45% had a partial response or better (at least a 25% reduction in YBOCS score). Postoperative adverse effects included headache, nausea, and difficulty with urination, usually resolving within days. Three of 44 (7%) patients had enduring sequelae: 1. seizures responsive to anticonvulsants, 2. worsened pre-existing urinary incontinence, 3. edema and hydrocephalus requiring ventriculostomy. In addition, 2 of 44 (5%) reported worsened memory and 1 of 44 described apathy and decreased energy, all resolving by 1 year after surgery. In the same series, 1 of 44 (2%) with a prior history of severe depression and a presurgical suicide attempt died by suicide 6 years after cingulotomy, although OCD symptoms had improved. Formal testing has generally revealed no lasting cognitive impairment after cingulotomy for psychiatric patients; improvements have in fact been seen, perhaps because OCD or depressive symptom reduction facilitated test performance.
Subcaudate tractotomy (ST) was developed and is primarily used in the United Kingdom. Lesions are made in the brain using beta radioactive yttrium rods inserted into an area just below the head of the caudate called the substantia innominata. These rods have a half-life of approximately 60 hours and remain in the brain indefinitely. Typically in the first few weeks after the operation patients experience confusion. Approximately 50% of treatment-refractory OCD patients who undergo ST improve, however, there has been little research done on the long-term effect of the radioactive implants.
Although more than 1,300 STs were performed in the U.K. between 1964 and 1993 for depression and OCD, systematic data were collected on only a small percentage of the total cases. Half of 20 severely ill OCD patients were either fully recovered or had slight residual symptoms three months postoperatively, though 4 of 10 responders relapsed within 2 years. Half of a second OCD patient sample responded after subcaudate tractotomy, again using global clinical measures. Adverse effects of subcaudate tractotomy included transient (≤1 week) headache, confusion, or somnolence. Transient postoperative disinhibition was described as common.
Limbic leucotomy(LL) was also developed and primarily used in the United Kingdom. It is a multi-target procedure that combines the techniques of ST and CG because it is believed that lesioning both the targets of the ST and CG are more effective than lesioning these areas alone. In a LL targets in the substantia innomiata and the cingulum are lesioned with radio-frequency heated electrodes, similar to those used in CG.
The first sample of OCD patients were reported to have an 89% improvement rate on global measures 16 months after limbic leucotomy, although that report was criticized as overly positive since many patients had significant residual symptoms. In the most recent report, where patients met criteria for severity and treatment resistance, 36-50% of patients were considered to have a clinically meaningful improvement after limbic leucotomy at Massachusetts General Hospital. Adverse effects of limbic leucotomy have included postoperative headache, confusion, lethargy, apathy, and incontinence, lasting from days to weeks. At an average 16 months postoperatively, 1 of 66 patients had severe memory impairment (associated with improper lesion placement), and 8 (12%) had persistent lethargy. IQ testing showed slight improvement after limbic leucotomy, likely due to reduced interference from symptoms of illness. In 21 patients having limbic leucotomy recently for OCD or depression at Massachusetts General Hospital under MRI guidance, apathy, urinary incontinence, and memory impairment were noted and described as infrequent and transient.
Gamma Knife Anterior Capsulotomy. Capsulotomies are also commonly performed via a method known as gamma knife radio surgery. The lesions in the brain are formed by concentrating cross-fired gamma irradiated beams at the target in the anterior limb of the internal capsule. Because of the relative lack of surgery, patients who receive gamma capsulotomy require little post-operative hospitalized care. There is also an instance for clinical research using gamma capsulotomy with a placebo or sham procedure unavailable with in the other procedures. Gamma capsulotomy can be studied using a placebo procedure because of the lack of surgical technique. Reports of gamma capsulotomy showed that the procedure was increasingly more effective with higher doses of radiation, but with these higher doses there were increased undesirable side effects (i.e. fatigue, apathy, disinhibition and the neuroradiological status of the patients was unstable). Both these procedures have the likelihood of affecting frontal lobe tissue. Effects of the frontal lobe may be present with an increase of side effects causing loss of inhibition and fatigue.
In prospective gamma capsulotomy studies conducted over the past 10 years at Brown University, 15 patients in the initial series received single bilateral lesions in the anterior capsule, made with a 4mm collimator, intended to interfere maximally with orbitomedial frontal-thalamic transmission. The average OCD duration was 15.5 years, and mean entry YBOCS score was 33 ± 5.1, indicating severe illness (for comparison, the mean entry YBOCS was 23, considered moderate severity, in patients entering multicenter SRI trials). Contrary to expectations, only 1 of the 15 improved by 6 months after single gamma lesions, suggesting a placebo response rate of <10% (a conclusive demonstration requires controlled data, which could not be obtained due to the excessive radiation exposure sham gamma knife surgery would entail). Later, 13 of the original 15 patients who failed to respond had a second bilateral lesion placed immediately ventral to the first lesion site. The target was the ventral-most capsule white matter, impinging upon the ventral striatum. Forty percent of those patients improved two years after surgery. This led directly to our second gamma knife technique, in which double bilateral lesions in the same locations are made on the same day. Our analysis shows an improvement from a baseline YBOCS of 35.3 ± 3.4 (severely ill) at baseline to 21.5 ± 10.3 (moderately ill) at 12 months. Two persistent adverse effects in 33 OCD patients receiving double bilateral gamma lesions were noted: 1) a mild frontal syndrome, with apathy and amotivation in 1 of 33 patients, persisting over five years, and 2) possible increase in manic episodes, which existed prior to surgery, in another. There were no group neuropsychological deficits.
While available data suggest that anterior capsulotomy, subcaudate tractotomy, anterior cingulotomy, and limbic leucotomy benefited roughly 30% to more than 50% of patients with severe, refractory OCD, no controlled data exist. Older reports were often retrospective, without current diagnostic instruments or validated rating scales making comparison across centers difficult. Samples were usually small, and only a single small study randomly assigned patients to different procedures, finding capsulotomy superior to cingulotomy in OCD. Recent prospective studies used better methods, but all were open trials. Without controlled data, the efficacy of any lesion procedure remains unclear.
