It isIt illegal to post this copyrighted PDF on any website. ([email protected]). PA 19125 Philadelphia, 305B, Ave, Suite 100 ELehigh Temple University, at Clozapine and TRS Clozapine and cognitive symptoms, supporting its diverse nature. symptom, but rather different combinations of positive, negative, rathervaried than uniform. Moreover, there is no pathognomonic Cochrane review Cochrane different etiologies. suggests that is aheterogeneous condition with established as gold the standard to treat TRS.Guidelines analysis a recent study has challenged conventional this wisdom. Ameta- and for terminology TRS. a consensus guideline on minimum the and optimum diagnosis address issue the of diagnostic ambiguity, aworking group created (392 mg/d) and lack the of a uniform criterion toTRS. To diagnose including an average clozapine dosage that considered could be low meta-analysis provideThe authorsthe limitations, several of statistically significant differences among various . establish clozapine as most ,the efficacious with few schizophrenia J ClinPsychiatry 80:4,July/August 2019 For [email protected]. reprints orpermissions, contact ♦ 2019 Inc. Press, © Copyright Postgraduate Physicians To https://doi.org/10.4088/JCP.18ac12394 share: Psychiatry treatment JClin options. cite: To 2019;80(4):18ac12394 J ClinPsychiatry * a A Justin Faden, DO of TreatmentA Brief Overview Options Treatment-Resistant Schizophrenia: treatment, with schizophrenia show alimited response to antipsychotic treatment for schizophrenia, approximately one-third of individuals these and other factors.these schedules, and as well cognitive as combinations difficulties, of for nonadherence include burden, side anosognosia, effect pill University, Philadelphia, Pennsylvania University, Philadelphia, greatest source of error unrecognized instudies on TRS. administration records) out to rule “pseudo-resistance,” possibly the sources pill (eg, counts, depot medication, plasma levels, medication medication adherence using should assessed be at also least 2 Brief PsychiatricScale, Systematic Rating Scale). monitoring of a standardized rating Positive (eg, scale and Negative Syndrome different classes). Symptom monitored to needs be severity using withepisodes different antipsychotic (not drugs necessarily from mg of chlorpromazine day, per and ≥ treatment with antipsychotic, each weeks of equivalent to ≥ from group the are that treatment failure should include ≥ comparing apples to oranges. Some consensus recommendations without uniform criteria, comparing studies on to TRSis akin Department of Psychiatry, Lewis Katz School of Medicine at Temple at Medicine of School Katz Lewis Psychiatry, of Department Corresponding author: lthough antipsychotic medications have mainstay the been of Since pivotalthe study by Kane et al, Faden J. Treatment-resistant schizophrenia: a brief overview of of overview abrief schizophrenia: Treatment-resistant J. Faden 6 assessing the efficacy of antipsychotics assessing efficacy the for TRS tofailed Leslie L. Citrome, MD,Leslie L. MPH, Editor Corner Psychopharmacology Clinical of Society American 1 treatment-resistant hasto which treatment-resistant term led the (TRS). 5 for TRS have generally However, this. confirmed 2 Justin Faden, DO, Lewis Katz School of Medicine Medicine of School Katz Lewis DO, Faden, Justin In addition, symptoms of schizophrenia are also a, 2 * The static failure to respond to treatment 8 7 The working group concluded that . 2019;80(4):18ac12394. . 2 past adequate treatment 3 clozapine has been 7 Reasons Reasons 4 and a a and 600 6 at adosage of situations. 30–40mg/d, inselected utilized can be alternative antipsychotic considered. can be High-dose olanzapine, tolerate or is refusing clozapine, monotherapy high-dose with an established treatment option. However, if an individual is unable to Treatment Alternatives for TRS dopaminergic neurotransmitters responsible could be for TRS. synthesis capacity. However, recent studies have suggested that non- schizophrenia, there is an increase in striatal presynaptic dopamine glutamatethe hypothesis of schizophrenia. In individuals with Glutamate ofSchizophrenia Hypothesis reducing excess dopamine mesolimbic signaling inthe pathway. thus NMDA alleviating receptor hypofunction and consequently as an NMDA receptor modulator by increasing levels and Clozapine is unique from other antipsychotics inthat it may function dopamine release downstream mesolimbic inthe pathway. hypofunction, with net the result pathologically being increased with schizophrenia are hypothesized to have NMDA receptor of must which present be inorder for activation to occur. complex, containing binding sites for glutamate and glycine, both labeling can provide additional efficacy. there to is suggest evidence that dosing higher than approved the in treatment-resistant or severely patients ill with schizophrenia, Although maximum the approved dosage for olanzapine is 20 mg/d, cortex. demonstrate increased levels of glutamate anterior inthe cingulate TRS did not have elevation expected the in dopamine, did they agents—our current treatment mainstay. Although individuals with elevation in dopamine that would respond to dopamine-blocking that patients may treatment be resistant lack classic the they because lower than levels the from antipsychotic responders. This suggests not statistically different from control levels but were significantly In individuals dopamine with TRS,striatal synthesis levels were range inthe effect of 600–838ng/mL. although there upper is no defined limit, there may a ceiling be of 350–420 ng/mL; however, it may as as500 ng/mL, high be and indicates that threshold the for therapeutic response is range inthe steady-state levels helpful, trough can be serum and most evidence optimizing clozapine treatment cannot overstated. be Monitoring guidance on what to doafter clozapine failure, importance the of unique therapeutic advantages of clozapine. Given lack the of clear reduced mortality inclozapine-treated TRSpatients reinforces the mortalityhigher during treatment with other antipsychotics. The with noby antipsychotic periods treatment, with nonsignificantly clozapine-treated individuals. results These were primarily driven individuals with TRSnot demonstrated a2-fold all-cause mortality higher rate among Despite recent controversy, clozapine for TRSremains most the An explanation for clozapine’s may rest superior efficacy with Despite clozapine’s challenging safety profile, A key is N-methyl- the d-aspartate (NMDA) © 2019Copyright Physicians Postgraduate Press, Inc. 12

treated with clozapine compared to 11 14 9 one study 13 Persons

1 13 10 12 14

You are prohibited from making this PDF publicly available. as augmentation strategies. reuptake inhibitors like and bitopertin, have studied been findings but will need to be duplicatedfindings but to be need will inaTRSpopulation. augmentation in schizophrenia showed similar symptoms of TRS.Ameta-analysis as anefficacious augmentation strategy for positive the and general negative symptom response. monotherapy and no significant difference in neurocognitive or in dropouts ECTgroup the between and receiving those clozapine towas treatment added their regimen. There were no differences ng/mL). ECT-treated subjects showed arobust response ECT when response to clozapine (average dosage 525mg/d, plasma level 854 to augmentused therapy inindividuals with TRSand an insufficient nonspecific patient with schizophrenia. toevidence recommend any one augmentation strategy for a publication and author biases, meta-analysis the found insufficient and overallquality methodology inthe study quality, and in schizophrenia. on heterogeneity the Based of studies, variable common augmentation strategies to antipsychotic monotherapy ( controlled conducted all heterogeneity with in China, high trials, Justin Faden augmentation and clozapine monotherapy. outliers, there was no significant difference lamotrigine between discontinuationhigher rate. With lamotrigine, after removal of 2 as general psychopathology, but is not recommended due to a found for effective to be positive and negative symptoms, as well capacity compared to average the Westerner. was also and average the person has alower Chinese clozapine metabolic 2 For [email protected]. reprints orpermissions, contact ♦ augmentation strategies. Arecent meta-analysis optimization of clozapine treatment, previously, as discussed and respond to clozapine, demonstrating for need the both Augmentation for Options TRS reinforcing importance the of optimizing clozapine. strategies following clozapine failure are promising but inconclusive, forshows positive symptoms. efficacy Glutamatergic augmentation fits all” approach. ECT has promising data in 1 study, and CBT addressed rathershould than specifically utilizing be a“one size symptom varied the presentation of TRS,individual symptoms supportsSome evidence olanzapine high-dose for to TRS.Due Conclusion were sustained at follow-up ranging from 3months to 2years. significant improvement compared when to controls. The results showedtrials that individuals with TRSreceiving CBT showed Glycine analogs such as d synergistic effects with clozapine.synergistic effects mixed findings on cognitive symptoms. showed for effective to be negative symptoms, with A memantine augmentation study for clozapine-refractory patients receptor and perhaps moderate glutamate-mediated excitotoxicity. TRS. Minocycline and memantine modulate NMDA the glutamate augmentation strategies for negative the and cognitive symptoms of of schizophrenia. foreffective general psychopathology and positive the symptoms TRS demonstrated that valproate sodium (800–1,125mg/d) was antiepileptic augmentation drug for clozapine-treated patients with It isIt illegal to post this copyrighted PDF on any website. I 2

= Cognitive behavioralCognitive therapy shown (CBT) has been to be As many as 40%–70%of TRSpatients fail to sufficiently will For individuals with TRS,clozapine should considered. be Electroconvulsive therapy shown (ECT) has been to have Medications targeting glutamate have as utilized been A meta-analysis of randomized controlled studies of

91%). Clozapine 5 levelstrials, werethe tested in only 1 of 16 However, study this 5randomized utilized -serine and-serine d 1,13 19 In arandomized study, ECTwas 20 of 12randomized controlled 15 -cycloserine, and-cycloserine, glycine 16 17 A meta-analysis of 15 evaluated 42 18

8. 7. 6. 5. 4. 3. 2. 1. Funding/support: None. interest: of conflicts Potential Published online: 20 19 18 17 16 15 14 13 12 11 10 9. REFERENCES ......

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