I. Definition
The treatment of refractory schizophrenia (treatmentresistantschizophrenia, TRS) has been one of the most difficult and popular research topics in the field of psychiatric therapeutics. Approximately 25–30% of patients with schizophrenia have TRS (ConleyRRetal, 2004). Refractoriness”, also known as “treatmentresistant”, refers to the failure to achieve the desired outcome with conventional treatment. There is a continuum between treatment efficacy and so-called refractoriness, and it is difficult to draw a clear line between them. However, the understanding of “refractory” varies from time to time, depending on the level of expectation of treatment and the treatment method. When assessing outcomes, it is important to consider not only the degree of improvement in psychopathological symptoms, but also meaningful improvements in subjective health status, ability to care for oneself, psychosocial functioning, or effort to participate in treatment. A comprehensive outcome assessment should include information on psychopathology, social functioning, quality of life, medication adherence, subjective patient experience, and risk/benefit ratio. Therefore, the definition of TRS should be multidimensional. However, in order to facilitate clinical research needs, scholars at home and abroad have proposed some evidence-based and operable definitions of TRS. Zheng Yingjun, Psychiatry Department, Guangzhou Brain Hospital
The current definition of TRS, which is relatively widely accepted at home and abroad, was proposed by Kane in 1996 after revising the previous concept based on his clinical experience. The specific points are: poor response to treatment with 3 antipsychotic drugs (at least 2 of the 3 drugs have different chemical structures) at appropriate doses and courses within the past 5 years; patients cannot tolerate the adverse effects of antipsychotic drugs; relapse or worsening of the disease even with adequate maintenance treatment or prophylaxis. In terms of drug dose and duration of treatment, Kane et al. (1996) concluded that all 3 antipsychotics need to have reached a high dose equivalent to 600 mg/d of chlorpromazine, with no improvement after at least 8 weeks of maintenance treatment, to be called TRS.
To simplify decision-making, many treatment guidelines, such as the American Psychiatric Association guidelines (2004) and the Texas Pharmacotherapy Specifications Program (2003), consider a patient treated with 2 or 3 atypical antipsychotics for at least 4 to 6 weeks with no response to be considered TRS.
Among other views, MinzenbergM, J, et al. (2008), an American, interpreted adequate dose and full course of treatment as adequate daily compliance with 400-600 mg clozapine equivalent of antipsychotic medication maintained for 4 to 6 weeks. In contrast, Liu Tiebang et al. in China pointed out that the dose of antipsychotic drug treatment need not be overemphasized due to the influence of individual differences, and it is not necessary to overemphasize whether the treatment was ever given in superconventional doses, but the number of drug species used in the past can be judged according to the two indicators of whether it reached the effective blood concentration and whether it reached the regular effective dose, and the two drugs with different chemical structures were systematically observed for 12 weeks, and if they were ineffective, they were treated as TRS.
With regard to the criteria used to assess efficacy, the criteria used to assess whether the treatment is effective or not is also an important defining parameter to determine whether it is refractory. The current common practice is to use psychopathological indicators, such as the Psychiatric Symptom Inventory before and after treatment, to observe whether there is a statistically significant improvement in psychiatric symptom scale scores after a certain period of treatment, or to use the rate of reduction as an indicator. The subtraction rate is calculated by dividing the difference between the pre- and post-treatment scale scores by the pre-treatment scale score, and multiplying the quotient by 100%. In a study by Kane et al. (1988), validity was defined as a 20% or greater reduction in BPRS scores after treatment, with a clinical global impression (CGI) scale less than or equal to mild, or a BPRS score ≤35. Recently, some authors (Bondolfi et al., 1998) have used the efficacy index (effectsize) as an index to assess efficacy, which is calculated by taking the difference between the pre- and post-treatment scale scores as the divisor and dividing it by the standard deviation of that difference. It is generally accepted that if the efficacy index is less than 0.2, it should be regarded as ineffective, 0.2 – 0.5 as minimally effective, 0.5 – 0.8 as moderately effective, and more than 0.8 as strongly effective. In the above-mentioned studies in which improvement in psychiatric symptoms was used as an indicator of efficacy, the severity of symptoms at the beginning of treatment had a significant impact on the judgment of symptom improvement, and it is apparently controversial whether the reduction of the BPRS total score from 70 to 56 (20% reduction) is equivalent to the reduction of the total score from 40 to 32 (also 20% reduction) by different researchers.
II. Mechanisms of refractory schizophrenia and related factors affecting the efficacy of treatment
1. Biological factors
Cai et al. (1997) found that mutations in the CYP2D6C188T locus may play a genetic role in the development of TRS, increasing susceptibility to the disease, and given that the CYP2D6 gene is located on chromosome 22 (22q13,1), it is suggested that 22q13,1 may exist. Ozaki (2004) also found that CYP2D6 fast metabolizing phenotypes (e.g., genotype T/T) cause accelerated metabolism of the drug in question, resulting in relatively lower blood levels, which may be an important factor in the refractory nature of schizophrenia.
Reelin is a glycoprotein, a matrix protein synthesized and secreted by cortical γ-aminobutyric acid (GABA)-ergic interneurons, which is involved in the migration and localization of developmental neurons and synaptic connections during neurodevelopment and may also modulate neuronal plasticity throughout life in a study by Goldberger (2005), who concluded that treatment resistance is associated with abnormal neurodevelopment and that antipsychotic drug The association between antipsychotic response and reelin gene polymorphisms was demonstrated by a higher frequency of (CGG)(10) alleles and genotypes in patients with good antipsychotic efficacy, suggesting an association of reelin gene variants with schizophrenia and also suggesting that reelin may be associated with refractory schizophrenia.Yu et al. (2008) found that patients with chronic schizophrenia had DNA telomeres of length was shortened in patients with chronic schizophrenia, and such patients responded poorly to antipsychotic drugs. Therefore, telomere shortening in chronic schizophrenia may be a characteristic marker of oxidative stress, and the subsequent abnormal cellular function may be a factor in the progressive deterioration of refractory schizophrenia. la et al. (2007) found that apolipoprotein A-1 was reduced in patients with refractory schizophrenia, implying a possible link between apolipoprotein A-1 and the pathology of schizophrenia. There is growing evidence that the neuro-immune-endocrine interconnections in schizophrenia may be damaged. Patients with refractory schizophrenia have elevated serum levels of cortisol, IL-2 and IL-6. Stassen et al. (2007) also suggested that patients with refractory schizophrenia are accompanied by activation of the inflammatory response system and significant alterations in T-lymphocyte function. Abnormalities in brain structure and function may underlie treatment resistance in schizophrenia, with studies showing a negative correlation between the degree of ventricular enlargement and treatment response, poor treatment outcome in schizophrenic patients with enlarged ventricles, and an increased ventriculo-brain ratio (VBR) associated with poor outcome.Molina et al. (2007) found that clozapine may correct schizophrenia-related deficiency states of the underlying substances or even somehow compensate for abnormal changes in distant septal sites. Clozapine treatment was associated with reduced metabolism in the prefrontal area and its subcortical connections and caudate nucleus and reduced thalamic activity in patients with refractory schizophrenia.Hoptman et al. (2005) found that dysfunction of the orbitofrontal cortex was associated with some abnormal behaviors in schizophrenia. Increased right orbitofrontal cortical volume was associated with poor neuropsychological functioning, and increased left orbitofrontal cortical gray matter volume and bilateral orbitofrontal cortical white matter volume were associated with the degree of aggression. Refractory patients have been found to show relatively more severe cortical atrophy on brain MRI imaging compared to schizophrenic patients with better treatment response (Stemetal, 1993) and possibly abnormal cortical cell migration (Kirkpatricketal, 1999). However, Friedman et al. (1992) analyzed that structural brain abnormalities do not predict the efficacy of antipsychotics.
In addition, the transport activity of the blood-brain barrier may affect the efficacy of antipsychotic drugs by influencing the intracerebral blood concentration. p glycoprotein (Pgp) is an important drug release carrier that binds to most antipsychotic drugs, and differences in the activity of this protein may affect the intracerebral blood concentration distribution. For example, competitive inhibitors of Pgp can reverse multi-drug resistance in cancer cells and bacteria. In contrast, clozapine is not transported by Pgp and intracerebral concentrations are not affected by Pgp activity, which may become a plausible explanation for the greater effectiveness of clozapine in treatment-refractory patients. The possibility that blood concentrations do not correspond to intracerebral drug concentrations in some TRS patients should be considered. Therefore, adjuvant therapy that attempts to increase the intracerebral concentration of antipsychotics may be beneficial for refractory patients.
2. Psychosocial factors
Poor patient compliance with treatment, high incidence of negative life events, inadequate social support, poor premorbid social functioning and autonomy, hostility, different cultural background from where they live, and work and life stress constitute common psychosocial factors (Caspi, 2007). Studies have found that patients with schizophrenia have a poor prognosis in families with high emotional expression, families with lack of care or support, or families with higher levels of stress.
3. Factors of the disease itself
Early-onset dementia as described by Kraepelin clearly falls within the range of refractory. keefe et al. (1990) emphasize the early onset, the presence of severe decline in multiple functions, poor response to antipsychotic medications, concomitant structural brain abnormalities, a propensity for schizophrenia spectrum disorders in first-degree relatives and a subtype with more negative symptoms, and a poor prognosis for core schizophrenia with a chronic progressive course. Patients with schizophrenia of the monotypic, residual type and with obsessive-compulsive and hypochondriac symptoms often have a poor treatment response. Moreover, patients with schizophrenia often have co-morbidities such as substance abuse, personality disorders, depressive disorders, and panic disorders, which complicate and make treatment more difficult. There is evidence that co-occurring personality disorders, obsessive-compulsive symptoms, substance abuse, etc. often lead to difficult treatment of the disease.
4.Other related factors
On the part of the physician: ① Wrong diagnosis at first onset. ② Failure to detect and treat early, or inadequate treatment at first onset. (3) Inappropriate use of drugs: e.g., the dosage is too low to reach the level required for treatment; or the dosage is too high and the side effects are too great for the patient to tolerate; or the duration of medication is not sufficient to affect the therapeutic effect.
Patient side: ①Lack of self-awareness or non-compliance with treatment. ②Small age of onset. ③Long time interval between onset and start of treatment (delay in treatment). ④Negative symptoms are prominent. ⑤Incognito onset. (6) Combination of somatic diseases.
III. Treatment strategies for refractory schizophrenia
For patients with TRS, the following principles should be followed first when starting to consider their treatment options.
① Review of the diagnosis.
Revisit the medical history and perform somatic and psychiatric examinations to determine whether the diagnosis is correct and whether there is a combination of substance abuse, personality disorders, and somatic disorders. A correct diagnosis is a prerequisite for effective treatment, and a prone error in TRS treatment is incomplete diagnosis. Marcus et al. (1990) found that 70% of refractory patients had a personality disorder, and Shaner (1993) reported a lifetime substance abuse co-morbidity rate of 50% in schizophrenic patients; there is also a proportion of patients with mental retardation. Re-evaluation must identify possible co-morbidities and suggest appropriate treatment for these co-morbidities when possible.
②Review past medication history.
Assess the duration of previous and current medications, dosage, patient compliance, and the presence of factors affecting efficacy. Is there a need to increase the dosage or extend the course of treatment or combination of medications, etc.? Did the patient receive medication early in the course of the disease? Were previous medications given in sufficient quantity and duration? Is there sufficient maintenance therapy? Are any of the drugs used relatively effective or have particularly significant side effects? Is the patient compliant and is the family supportive of treatment? If there is a positive family history, what drugs are effective in affected relatives? Did previous treatment include active psychosocial interventions? Reviewing the history of previous treatment can help to reformulate proven comprehensive treatment measures.
(iii) Review of refractory cases, with blood levels measured if necessary.
Review strictly in accordance with the criteria for refractory schizophrenia, and perform refractory testing and re-determination if necessary if information is incomplete. In refractory schizophrenia, testing blood drug concentrations can clarify the patient’s compliance with medication and whether the patient has problems with drug metabolism.
④ Develop a systematic and comprehensive treatment plan.
Once the existence of refractory phenomena is clearly identified, the causes of refractoriness should be identified and an orderly and systematic treatment plan should be developed also to clarify the target symptom clusters that form the manifestation of treatment resistance, to maintain a positive attitude toward treatment, and also to take into account the presence of factors that are unfavorable to psychosocial treatment approaches. The development of a treatment plan can be informed by reference to national guidelines for the treatment of schizophrenia. Reference can also be made to the currently widely accepted treatment protocol for schizophrenia proposed by the US TMAP (2006), in which treatment protocols from stage 3 onwards can be considered as TRS-recommended treatment protocols.
(iii) Reformulation of medication regimen
In terms of pharmacological treatment of TRS, the most evidence-based treatment drug is clozapine, but studies have demonstrated that the efficiency of clozapine alone in the treatment of refractory schizophrenia is only 30–50% (ConleyRRetal, 2001; KaneJetal, 1988). On the one hand, clozapine is of great importance in the treatment of TRS. On the other hand, we can see that 50% – 70% of TRS patients treated with clozapine in full dose and duration are still ineffective. This group of TRS patients who are not treated with clozapine is called “clozapine-resistant TRS” or “super TRS”. For these patients, pharmacologic and non-pharmacologic augmentation strategies are still the best options available.
Conley et al. noted that olanzapine was only 7-17% effective in refractory patients, and even high-dose olanzapine (30-60 mg/day) regimens have not been shown in trials to improve outcomes in patients with TRS. In patients with TRS, the effect of single-agent dose increases is limited (with the exception of clozapine).
Although the benefits of potentiating treatment strategies with combinations between antipsychotics remain inconclusive (Mouaffak 2006), multiple antipsychotic combinations remain common in clinical practice for patients with TRS, particularly clozapine-resistant TRS (Gupta 2008).
1. In-depth thoughts on clozapine treatment
Clozapine has shown relatively good efficacy on negative and positive symptoms of TRS, including excitement, impulsive aggression, violent behaviors such as suicide, and psychosocial withdrawal. The efficacy of clozapine in the treatment of refractory patients is not only superior to that of conventional antipsychotics, but also to that of other non-classical antipsychotics, and it is recommended that it should be started as early as possible once TRS is identified. The sustained improvement of clozapine treatment can sometimes be extended to the sixth month or even longer. In the trial by Fitton et al, the remission rate was found to be related to the duration of treatment, with the remission rate in the clozapine group being 30% at 6 weeks, 45% at 10 weeks, and 54% at 26 weeks. Therefore, some scholars suggest that the course of clozapine should be more than 6 months when dealing with TRS and should not be easily abandoned.
The clinical efficacy of clozapine is linearly correlated with the blood concentration level, and the blood concentration has a significant effect on the efficacy. Several studies have shown that the efficacy is significant at blood concentrations of 350–420 ng/ml. In contrast, Pakin et al. concluded that the therapeutic threshold level of clozapine blood concentration is around 450ng/ml, and he found that 60% of patients above this level showed efficacy within 4 weeks, while only 8% of patients below the changed level showed efficacy. This study suggests that an appropriate increase in clozapine dosage to 600-800 mg/d, depending on blood levels and patient tolerance, may lead to further improvement in the efficacy of some TRS. Of course, there are also results from studies that would like to argue the opposite that there is no significant correlation between the efficacy of clozapine and dose.
In terms of clozapine combination, it is recommended to combine antipsychotic drugs with different drug structures and mechanisms, especially sulpiride is considered to have a better synergistic effect. Clozapine combined with sodium valproate for TRS has a synergistic effect in the short term, but long-term efficacy has not been demonstrated. All other drugs combined with potentiation therapy lack sufficient evidence.
It should be noted that clozapine has a high number of adverse effects, some of which, such as granulocyte deficiency, are fatal. The more common adverse reactions include salivation, constipation, blurred vision, sedation, malaise, weight gain, cardiac arrhythmias, hypotension, fever, and elevated granulocytes, while less common adverse reactions include obsessive-compulsive symptoms, convulsions, confusion, and granulocyte deficiency. Therefore, very close observation is required during the administration of the drug. The wide variety of adverse reactions largely limits the widespread use of clozapine.
2. Combined medication treatment
(1) The combination of two antipsychotic drugs.
FreudenreichO et al. (2002) compared the efficacy of combined medication with that of medication alone through a meta-analysis of two randomized double-blind controlled trials and six open-label trials. The results found that clozapine combined with sulpiride assessed BPRS efficacy better than monotherapy in half of the patients in the randomized double-blind controlled study, whereas clozapine combined with chlorpromazine treatment showed no significant difference in efficacy with monotherapy. The results of open-label clinical trials of clozapine combined with risperidone lacked consistency, with only some trials showing significantly better outcomes than clozapine alone. It is believed that the combination of clozapine and other multi-receptor acting agents (MARTAs) with drugs that have a higher selective affinity for D2 receptors by different mechanisms, such as sulpiride, may improve the efficacy. In addition to clozapine MARTAs include olanzapine, quetiapine, and levotepine (zotepine). Based on pharmacologic effects, sulpiride has also been considered as an alternative to amisulpride in attempted combinations with MARTAs.
Other forms of combination lack sufficient evidence of consistency.
Excessive combination of drugs may aggravate adverse drug reactions and even increase the chance of serious adverse reactions such as malignant syndrome and delayed dyskinesia, and therefore should be decided with great caution and closely observed.
(2) Antipsychotics combined with mood stabilizers.
In 2003, Casey et al. conducted a double-blind controlled trial in 249 patients with schizophrenia to compare the synergistic effects of combining olanzapine with valproate, and concluded that the antipsychotic combined with valproate group showed significant improvement in positive symptom scores of PANSS and BPRS on both day 3 and day 21 compared with the group on medication alone. However, at day 28, there was no significant difference in improvement between the antipsychotic alone and the combined group. Atypical antipsychotics combined with sodium valproate were effective in improving positive symptoms only in the early phase of drug administration, but the efficacy of long-term combined drug administration in improving symptoms is unclear.
In contrast, in 2002, LeuchtS et al. conducted a review and analysis of eight clinical trials (220 cases in total) related to the effectiveness of antipsychotic drugs combined with carbamazepine in the treatment of schizophrenia. The results found that there was no significant difference between the combination of positive symptoms, negative symptoms or depressive symptoms and the medication alone. It was concluded that there was no significant difference between the efficacy of antipsychotic drugs combined with carbamazepine treatment and the efficacy of antipsychotic drugs alone.
In 2003, LeuchtS et al. conducted a meta-analysis of 20 papers (270 cases in total) from randomized controlled trials related to the effectiveness of antipsychotic medication combined with lithium carbonate in the treatment of schizophrenia. The results found that the rate of shedding was significantly higher in the combined lithium carbonate group than in the antipsychotic group alone, and there was no significant difference in efficacy between the two groups for comparison. Among them, combined lithium carbonate treatment showed better improvement in efficacy only in patients with coexisting affective disorders than in the drug-alone group, and if this factor was excluded, the efficacy showed no difference between the two groups. It is believed that the combination of lithium carbonate treatment makes no difference in the efficacy of schizophrenia patients without affective disorder symptoms, but rather reduces treatment compliance.
(3) Combination of antipsychotics with antidepressants.
Combination antidepressant therapy may be attempted in those with depression, poor mood, negative behavior, or those with persistent negative symptoms. 1998,1999,2004; Goffetal,,1995b; Evinsetal,,2002), but the exact pharmacological mechanism of action needs to be further investigated. However, an increased risk of adverse reactions has been reported when atypical antipsychotics are combined with SSRIs.TakafumiHori et al. (2006) suggested that drug interactions between olanzapine and fluvoxamine increase the risk of serious adverse reactions. Many scholars are still negative about the combination of antidepressants for TRS because of the lack of sufficient evidence-based medical evidence.
(4) Benzodiazepines: The combination of benzodiazepines, such as alprazolam, may provide temporary relief of euphoria, agitation, anxiety and other symptoms, but there is no credible evidence-based evidence for the therapeutic effect on the core symptoms of TRS.
(5) Other drugs and new drugs in clinical trials.
(1) Free radical scavengers: It is believed that catecholamines, especially norepinephrine, and their autoxidation can generate free radicals, which can damage neurons, cause nerve damage and aggravate negative symptoms. Long-term use of S1TL and S1TU can scavenge free radicals and may be effective.
Glycinetype1transporter (GlyT1): This class of drugs has been synthesized in large quantities, including: ALX-5407/NFPS, NPTS, Org24462/Org-24598, Lunbeck preparation and R213129. The synthesized second-generation GlyT1 blockers are able to enhance NMDA function while inhibiting glutamate release, and on the other hand, inhibit dopaminergic neurological transmission, and may be used alone to obtain satisfactory therapeutic effects. Drugs with this mechanism have become a hot spot for new drug development at present.
(iii) mGluR2/3R agonist: Patil et al. (2007) compared the efficacy of mGluR2/3R agonist LY2140023 with that of olanzapine and found no significant difference in PANSS score reduction rate after 4 weeks with olanzapine. No side effects such as weight gain, hyperprolactinemia and EPS were found in terms of safety.
Dursun and Deakin used the AMPA receptor antagonist lamotigine as an adjunct to clozapine in patients with refractory schizophrenia and found a significant improvement in BPRS scores. There was a significant improvement in symptoms.
⑤ α7nAchR partial agonist: Recently, Sanofi-Aventis has synthesized α7nAchR partial agonist with the number 180711. This drug is able to increase Ach release in the hippocampus and prefrontal lobes while enhancing glutamatergic neurotransmission and promoting cognitive function. This drug is considered to be a possible very promising candidate for improving cognitive function and depressive status in schizophrenia.
(vi) Other drugs: Several studies are currently exploring the efficacy of various drugs for refractory schizophrenia, particularly for negative symptoms and cognitive function. Drugs still being explored include dehydroepiandrosterone (Strousetal, 2003), propargylamphetamine (Jungermanetal, 1999), galantamine (RosseandDeutsch, 2002), ginkgo biloba extract (Zhangetal, 2001), methylene blue (Deutschetal,, 1997), naltrexone (Marchesietal,,1995), silybin (Bodkinetal,,1996; Guptaetal,,1999), and pergolide (RoeschElyetal,,2006). However, the exact efficacy of all these drugs needs further study and their use is not recommended yet.
(iv) Psychosocial treatment
The contemporary view is that psychosocial treatment constitutes an essential element in the treatment of all patients with schizophrenia, and the treatment of TRS is certainly no exception. There is a growing recognition of the relevance of comprehensive and integrated interventions that include individual psychotherapy, family psychotherapy, and social support to maximize the benefits for patients with schizophrenia, especially those with very severe conditions (Lerootetal, 2003). Given that the focus of care for the most severely ill patients with chronic TRS is gradually shifting from large public hospitals to the community, the importance of comprehensive and integrated interventions that include psychosocial treatment is also increasing.
Psychosocial treatment mainly includes case management and proactive community therapy, cognitivebehavioral therapy (CBT), supportive psychotherapy, family psychotherapy, cognitive remediation and rehabilitation, and psychiatric rehabilitation. Here, we will focus only on CBT.
More than 20 randomized controlled studies of CBT for the adjunctive treatment of schizophrenia have so far shown that it is effective for patients with positive and negative symptoms as well as depressive symptom clusters, and some of these studies have shown that CBT is effective for patients with TRS. the essential point of CBT techniques as an effective adjunct for the treatment of refractory patients is to promote the recovery of the patient’s self-knowledge. kuipe (1996) describes a CBT model. Treatment addresses three important goals or any of them: (i) reducing distress and disturbance caused by psychopathic symptoms such as delusions and hallucinations; (ii) increasing the patient’s understanding of the psychopathic disorder and developing self-regulation; and (iii) reducing the occurrence of mood disorders and pessimistic, self-abandonment behaviors caused by disappointment and self-denial.DavidKinon et al. (2000) argue that CBT should be used as a foundation in the treatment of A meta-analysis conducted by ZimmermannG, et al. (2005) showed that CBT can result in a significant reduction or alleviation of positive symptoms. Most studies examining the use of CBT in schizophrenia have concluded that approximately 20 sessions are required, each lasting 1 hour or less, suggesting that CBT is not short-term but requires a long-term, continuous, systematic course of treatment.
Of course, CBT is not effective for every patient, especially those with very severe psychotic symptoms, and CBT is not recommended if the degree of paranoia, avoidance, or cognitive impairment does not allow them to participate in effective CBT treatment.
(V) Physical therapy methods
1. Combined electroconvulsive (ECT) therapy
Some previous studies have confirmed that the near-term efficacy of ECT combined with antipsychotics is better than that of ECT alone or antipsychotics alone, suggesting that the combination of ECT and antipsychotics has a synergistic effect in acute and subacute states. ECT treatment is recommended for acute and subacute states of TRS, especially for the rapid treatment of catatonic symptoms (TharyanandAdams, 2005). The combination is relatively effective in patients with arousal-aggressive behavior and affective disorders. eCT treatment has gained considerable improvements over the years and the modified mECT has the advantage of being safe and reliable and has reduced side effects to the minimum possible. However, short-term cognitive impairment is still relatively common in its use. eCT has its limitations, its use is restricted in many cases, and it has not shown significant advantages over pharmacotherapy in the maintenance treatment of TRS.
The current majority view is that ECT in combination with antipsychotics is indicated for patients with refractory schizophrenia, but should not be used as first-line therapy and may be used as a second or third-line treatment measure. There is no consensus on how many sessions of ECT should be effective in refractory schizophrenia. 6 – 12 sessions of conventional treatment is generally a course of treatment, but the number of sessions should be increased appropriately in refractory schizophrenia. friedel (1986) suggested that ECT has significant efficacy in refractory schizophrenia, with The average number of treatment sessions to show efficacy was 13,6. This number can only be used as a reference, and so far there is no double-blind controlled trial results to support it.
2. Combined repetitive transcranial magnetic stimulation (rTMS)
rTMS is currently being evaluated as another form of biological treatment for patients with TRS, and this treatment has shown preliminary positive results in reducing the severity of refractory hallucinations (Huffmanetal2000). phantom hearing. This has been replicated by many studies. However, unfortunately, rTMS has not been convincingly documented in the treatment of negative symptoms and positive symptoms other than hallucinations and improvement in cognitive function.
(vi) Stereotactic surgery
Stereotactic surgery for refractory schizophrenia is a new technique of microinvasive treatment that uses a guidance system to deliver radiofrequency electrodes to the parts of the brain that may be associated with a certain mental activity for destruction, interrupting the connection between them and balancing the neurotransmitters in the brain to achieve the elimination or reduction of mental symptoms. The application of stereotactic surgery for the treatment of refractory psychiatric disorders has been widely reported at home and abroad, and many researchers consider this procedure as an effective means of treating refractory psychiatric disorders (Adolphs et al., 2005). However, it is worth noting that there are still many international scholars who oppose this treatment, and ethics will be a strong resistance to this treatment. Until the etiology of schizophrenia is elucidated and the true site and mechanisms of the lesions in the brain are understood, the vast majority of scholars remain negative about the treatment.
I conclude with a quote that I often use in my training and teaching of psychiatrists and students: “The most brilliant psychiatrist is the one who applies the least variety of medications after a precise diagnosis, treats the patient well in combination with a standardized psychotherapy approach, and gives much thought to reducing the risk of relapse, adverse drug reactions, and financial burden for them afterwards. —- Jung Young-jun “.