Obsessive-compulsive disorder (OCD) is undoubtedly one of the most disabling psychiatric disorders, leading to significant socio-occupational impairment and reduced quality of life. In many cases, the efficacy of “conventional” or “first-line” treatment is suboptimal; however, the true meaning of “refractory OCD” may be less than expected. This article briefly describes the biological treatment strategies for refractory OCD with the aim of providing clinical guidance. Definition of “refractory” A fundamental question is how to define “refractory”. Treatment regression is usually based on a reduced score on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), which rates obsessive-compulsive thoughts and behaviors in terms of time spent on OCD symptoms, mental distress, control, resistance to symptoms, and daily interruptions. However, what constitutes a response is controversial and is usually a percentage reduction, but even when such a percentage reduction does occur, some patients actually have significant symptoms and “response” is not true. Another indicator is remission, which is often difficult to achieve in the treatment of OCD. A Y-BOCS score of <14< span=""> is generally considered a reasonable threshold for remission, while a Y-BOCS score of <12 is used as an indicator of "good status" in treatment studies, and some studies have proposed a score of 10 as a threshold. However, symptom indicators do not necessarily correlate with disability, and disability-specific measures should also be included in the consideration of OCD treatment response. A generalized disability scale, such as the Sydheim Disability Scale (SDS), is sufficient as a macroscopic tool; however, more subtle exploration of the patient's psychosocial disability is needed for the purposes of holistic treatment. Monotherapy There is little debate about the first-line biological treatment options for OCD: the SSRIs class of drugs has a good track record of efficacy and tolerability, including fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram, and escitalopram. For example, the 20 mg group of escitalopram had a faster onset of action compared to placebo and its efficacy was superior to that of the 10 mg group. For OCD symptoms, SSRIs showed a slow, cumulative onset of action pattern, with symptom improvement compared to placebo beginning 1-2 weeks after initiation of treatment and continuing to increase over a period of at least 24 weeks. Transient exacerbations of anxiety early in treatment are rarely seen in acute phase studies of SRIs for OCD. A "reasonable" clinical study of OCD should last 12 weeks, as clinical benefits may take some time to accrue. There is insufficient evidence to suggest which SSRIs are most efficacious and well tolerated in the treatment of OCD. Overall, higher doses of SSRIs should be required for OCD than for depression. The current debate is that there is inconsistency in the literature regarding the absolute dose of antidepressants needed; and in some cases, maintaining regular doses of antidepressant therapy can ultimately be effective, and physicians may prematurely adopt aggressive dosing regimens. What is certain, however, is that if low doses of SSRIs are ineffective, it is wise to increase the dose and monitor efficacy and tolerability. Based on evidence from clinical trials, SSRIs can be increased to the following doses for the treatment of OCD: escitalopram: 60 mg; fluoxetine: 120 mg; paroxetine: 100 mg; sertraline: 400 mg. A recent meta-analysis showed that higher doses of SSRIs do have better efficacy for the treatment of OCD, but also at the expense of tolerability to some extent. Although higher doses may provide additional benefits for some individuals, it is important that physicians exercise caution in the context of overdosing to avoid dangerous side effects whenever possible; given recent concerns about the potential cardiac risks of high-dose citalopram, it is always a good idea to check the electrocardiogram (ECG) when using high doses of any of the above drugs. If treatment with high-dose SSRIs fails, clinicians are faced with the following dilemma: switch to another drug or continue to increase the dose? There are pros and cons to either option, but the general rule is: if the patient does experience some tangible benefit from the initial drug therapy, an increase in dose should be preferred; if there is no or minimal benefit from the initial drug therapy, it is wise to switch. However, there are some patients who do not experience a treatment response until months later. In clinical work, physicians often choose to switch to another SSRI medication, a move that works well in a subset of patients; however, there is still little research evidence on which patients tend to respond to which medication. A common scenario in the treatment of depression is that some patients who are severely depressed or who do not respond significantly to SSRIs switch to SNRIs, but there is little supporting evidence for this tool in the field of OCD treatment. For example, one study showed a poor outcome with paroxetine 60 mg treatment and no significant benefit from switching to venlafaxine 300 mg. That said, if depression is a prominent co-morbid feature of OCD, then SNRIs are not an unreasonable option. However, it is important to note that high-dose SNRIs may cause adrenergic side effects and discontinuation may also cause some problems, especially with venlafaxine. Evidence consistently shows that clomipramine is effective in the treatment of OCD. clomipramine differs from other tricyclics in that it has a stronger inhibitory effect on 5-HT reuptake, despite also having NEergic effects. Randomized controlled studies have demonstrated the usefulness of this tricyclic antidepressant in the treatment of OCD, but the doses required for treatment (up to 300 mg) can cause side effects that are difficult to tolerate, such as anticholinergic and sedative effects, so blood levels and electrocardiograms need to be monitored. Some evidence suggests that clomipramine is more effective than SSRIs in the treatment of OCD, but head-to-head studies are scarce. It is important to note that the side effects associated with chlorpromazine are so significant that a truly blinded design is difficult to achieve. Most guidelines recommend that clomipramine treatment be tried after trying two SSRIs at high doses has failed, due in large part to the fact that it is poorly tolerated. Intravenous chlorpromazine treatment was popular in some treatment centers: this move avoids first-pass metabolism and apparently may be particularly beneficial for a subset of patients; however, the cost prevents its use in routine clinical practice. Although some physicians claim that they would use conventional monoamine oxidase inhibitors (MAOIs) as a treatment option for OCD and report substantial therapeutic benefits with such drugs in some patients; however, the status of MAOIs for OCD has not been established. Whether antidepressants with novel mechanisms have a place in the treatment of OCD is similarly unknown. Case reports and case groups have reported that the melatonin M1/M2 receptor agonist and 5HT2 receptor antagonist agomelatine is effective in the treatment of OCD; it is generally well tolerated and may be a new option for patients who cannot tolerate SSRIs. However, to date, the optimal dose of this drug for the treatment of OCD has not been determined, and no indication for the treatment of OCD has been obtained. To our knowledge, the multi-receptor antidepressant vortioxetine has not been used for the treatment of OCD, but the effect of the drug against the 5-HT transporter suggests that it may have therapeutic potential; like agomelatine, vortioxetine does not have an indication for OCD and the dose of the drug for OCD has not been determined. Combinations Many patients with OCD do not respond adequately to first-, second-, or third-line monotherapy, making it necessary for clinicians to combine other medications. There are some general considerations when combining drugs, including drug interactions, and more serious side effects than with monotherapy. However, some combination strategies have a sound evidence-based basis and are mostly safe. A more prudent approach is to combine one drug at a time, carefully monitor efficacy and side effects, and discontinue any ineffective drug before combining with another. For antidepressants, the most established combination strategy is an SSRI + chlorpromazine, although the data are limited to small case-group or open studies and the evidence from randomized controlled trials is inconsistent. As the SSRIs in this combination, fluoxetine and citalopram have been validated in studies. Monitoring of clomipramine blood levels and routine electrocardiography are also recommended when using this combination regimen; in addition, there is a risk of 5-HT syndrome with this combination. The combination of an SSRI + another SSRI has also been used in clinical practice, but there are no robust clinical trial data to support this usage. An increasingly common combination strategy in the treatment of refractory OCD is an SSRI + an atypical antipsychotic. Early studies have shown that the combination of pimozide and haloperidol with fluvoxamine is more effective in patients with OCD with tics. A recent meta-analysis of randomized controlled studies showed sufficient studies to support the combination of an SSRI with risperidone in the dose range of 0.5-3.0 mg for OCD; at least in the short term, the combination of aripiprazole 6-30 mg was also effective, whereas the combination of olanzapine (2.5-20 mg) and quetiapine (50-600 mg) did not have this effect. In fact, quetiapine has a wide range of clinical applications and doses, with anxiolytic, antidepressant, and sleep-aid effects. Of course, the choice of specific drugs should vary from person to person. For example, while quetiapine is certainly useful for insomnia and generalized anxiety symptoms, aripiprazole is a wise choice for patients with drowsiness and weight gain. Since the exact dosage and duration of treatment of the drug are not fully established, individualization is necessary. Fineberg et al. provided a useful review on the pharmacological treatment of refractory OCD. They concluded that a number of drugs previously thought to be effective in the treatment of OCD have been verified to be ineffective in studies, including the combination of lithium carbonate, buspirone, indololol, desipramine, inositol, sumatriptan, and naltrexone. The combination of benzodiazepines? Among the classes, the combination of clonazepam has gained some evidential support, and the mechanism may be the 5-HTergic effect of the drug. In a 12-week placebo-controlled study, the anticonvulsant topiramate had some efficacy on obsessive-compulsive behavior but no significant efficacy on obsessive-compulsive thoughts. The combination of mirtazapine on top of citalopram 40-80 mg showed benefit only in the short term, and the mechanism may be the sedative effect of mirtazapine. Two recent studies suggest that the 5-HT3 receptor antagonist ondansetron (1-4 mg/d) has better efficacy and tolerability, and the related drug granisetron (2 mg/d) has the same potential. The glutamatergic nervous system is also emerging as a research hotspot for OCD treatment. One of the most studied is memantine: in a 12-week trial, patients who did not respond to SRI showed some efficacy when combined with memantine 5C20mg. The drug was well tolerated with no significant adverse effects. Riluzole also showed potential in smaller trials, but the drug's adverse effects causing pancreatitis limit its use. In exposure therapy, the clinical regression of co-administered D-cycloserine was inconsistent, and glycine also brought benefit in small case-group studies, but the nausea and unpleasant taste sensation induced by the drug led to a large number of subjects falling out of the study. Transcranial magnetic stimulation, psychosurgery and deep brain stimulation Transcranial magnetic stimulation (TMS) is commonly used in the treatment of depression, but its use in the treatment of OCD is more limited. A recent review of the literature showed promising results for OCD with TMS at 1 Hz in the anterior supplementary motor area and with deep TMS at 20 Hz. Clearly, further research is still needed. Psychosurgery has a long history of treating refractory OCD, but it is difficult to evaluate using the methods of randomized controlled trials. The gamma knife has now largely replaced traditional surgical techniques. In a recent randomized controlled trial, investigators performed gamma knife endocapsulotomy on eight patients with severe OCD. The results showed that at month 12, three subjects produced a treatment response, defined as a 35% reduction in Y-BOCS scores and improvement or significant improvement on the Clinical Global Impression-Improvement of Symptoms (CGI-I) scale, and two others were further defined as responders at 54 months of follow-up. In addition, two of the four subjects who initially received pseudo-treatment and then underwent open-label psychosurgery produced a response. As an emerging intervention for many disorders, deep brain stimulation (DBS) has emerged as a "reversible" alternative treatment option to surgical procedures. In patients with severe refractory OCD, DBS has been tested in several studies over the past 15 years, including at least 8 open-label studies and 6 RCTs using multiple anatomical targets including the anterior limb of the internal capsule and the ventral internal capsule/ventral striatum. While this treatment approach may result in 30-40% improvement in 50-60% of patients, the optimal target for individual patients has yet to be established. Given the fact that the current evidence is growing but still relatively limited, DBS is considered an experimental therapy for OCD. In addition to the treatment itself, the emergence of therapeutic effects depends on the optimization of patience and stimulation parameters, including voltage and stimulation frequency, as well as the combination with psychotherapy, including cognitive behavioral therapy (CBT). Conclusions Evidence from studies on how to treat patients with OCD who do not respond to first-line treatment is relatively scarce. It is undisputed that high-dose SSRIs and chlorpromazine have good evidence-based data. There is limited evidence for the combination of SSRIs, but there is evidence to support the combination of SSRIs with clomipramine, when monitoring of clomipramine blood levels and electrocardiograms is required. Although the combination of specific atypical antipsychotics is evidence-based and has been used clinically, it is not effective in all patients, so residual symptoms are still common; the combination of such medications must be weighed against the pros and cons. In patients with substantial generalized anxiety symptoms, clonazepam is worth considering. Other potentiation strategies, memantine and ondansetron, appear to be effective in some cases and are well tolerated. TMS may have a place in the treatment of OCD, but there is still little guidance on which patients may benefit and which sites are appropriate targets for treatment. If all of the above treatments plus specialized psychotherapy fail, DBS may be given after careful consideration, and this therapy may provide significant benefits for some patients. Gamma Knife psychosurgery may also be beneficial, but many treatment centers do not have this capability.