TREATMENT-RESISTANT SCHIZOPHRENIA: CHALLENGES AND IMPLICATIONS FOR CLINICAL PRACTICE

Despite pharmacological advances in the treatment of schizophrenia, significant number of patients continue to be treatmentresistant. Poor control of symptoms could be related to low concentration of antipsychotics because of non-adherence or pharmacokinetic issues. However, there is growing evidence that “true” treatment-resistance might be associated with biological changes, i.e. alterations in dopaminergic and glutaminergic systems, genetics, neurodegeneration and neuroinflamation. Clozapine is recommended as first-line treatment for treatment-resistant schizophrenia (TRS) in all guidelines. Clozapine-ECT combination is effective in majority of those patients, at least in short-term. However, more than half of patients with TRS have resistance or intolerance to clozapine, and more interventions are needed. Different combination and augmentation strategies may offer some advantage, but evidence is limited. Given the severity and complexity of TRS, there is an urgent need for better treatment. Treatment strategies beyond dopamine, such as glutamate-modelling agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal treatment, are under investigation

Psychiatric Comorbidity in Migraine

Iako su i migrena i psihijatrijski poremećaji vrlo učestali, relativno je malo literature o njihovom komorbiditetu. Visoka učestalost migrene utvrđena je u osoba s anksioznim poremećajima i bipolarnim poremećajem, no najviše podataka nalazi se o komorbiditetu migrene i depresivnog poremećaja. Ova povezanost tumači se zajedničkom etiologijom, poput genetske predispozicije, poremećaja serotoninskog sustava te sličnih psiholoških čimbenika, stoga ne iznenađuje da su neki antidepresivi pokazali povoljan učinak u oba poremećaja, prije svega amitriptilin, zatim duloksetin i venlafaksin, a moguće i mirtazapin i agomelatin. Budući da neki antimigrenici i mnogi antidepresivi utječu na različite komponente serotoninskog sustava, moguće su interakcije te je neophodan oprez. Psihoterapija također ima direktan učinak i na migrenu i na simptome depresije i anksioznosti. Valproat ima učinak na migrenu i na simptome bipolarnog poremećaja. Psihijatrijski komorbiditet u oboljelih od migrene još uvijek nije dovoljno prepoznat te neki autori čak preporučuju rutinski probir osoba s migrenom na simptome psihijatrijskih poremećaja, posebice depresivnosti i anksioznosti. Potrebno je istovremeno liječiti oba poremećaja. Najbolji je individualni pristup liječenju uz suradnju specijalista neurologa i psihijatara što svakako daje najbolje rezultate u granicama postojećih mogućnosti.Although migraines and psychiatric disorders are very common, literature on their comorbidity is quite scant. A high incidence of migraine has been detected in patients with anxiety and bipolar disorders, but most data are found on the comorbidity of migraine and depressive disorders. They are connected through a common etiology, i.e., genetic predisposition, serotonin system disorders, and similar psychological factors. It is not surprising that some antidepressants have exhibited a beneficial effect in both disorders, mainly amitriptyline, duloxetine and venlafaxine, and possibly mirtazapine and agomelatine. Because some antimigraine drugs and many antidepressants affect specific components of the serotonin system, interactions are possible and thus necessary precautions must be taken. Psychotherapy also has a direct effect on the migraine as well as symptoms of depression and anxiety. Valproate was reported to improve symptoms of both migraine and bipolar disorder. Psychiatric comorbidity in migraine patients is still incompletely understood, and some authors even recommend routine screening of patients with migraines for symptoms of psychiatric disorders, especially depression and anxiety. Both disorders need to be treated simultaneously. Therefore, the cooperation between neurologist and psychiatrist is the key to achieving the best results

Electroconvulsive treatment of patients with treatment-resistant schizophrenia and empty sella syndrome: two case reports

Empty sella is the neuroradiological or pathological finding of an empty sella turcica containing no pituitary tissue. Even though empty sella syndrome (ESS) and schizophrenia are both relatively common in the general population, to the best of our knowledge, there is only one similar case report regarding the co-occurrence of those two condition

THE COMORBIDITY OF BIPOLAR DISORDER AND CARDIOVASCULAR DISEASES FROM PHARMACOTHERAPY PERSPECTIVE

The heart and mind are intimately linked. Patients with severe mental disorders have increased mortality rates compared with the general population and the leading cause of premature death is cardiovascular disease (CVD). Despite their high prevalence and substantial medical impact, comorbidity between cardiac conditions and psychiatric illnesses frequently go undiagnosed and untreated. It is very interesting to investigate the impact of mental health on cardiac disease and what is the complex underlying mechanism that links theese two conditions

THE COMORBIDITY OF BIPOLAR DISORDER AND CARDIOVASCULAR DISEASES FROM PHARMACOTHERAPY PERSPECTIVE

The heart and mind are intimately linked. Patients with severe mental disorders have increased mortality rates compared with the general population and the leading cause of premature death is cardiovascular disease (CVD). Despite their high prevalence and substantial medical impact, comorbidity between cardiac conditions and psychiatric illnesses frequently go undiagnosed and untreated. It is very interesting to investigate the impact of mental health on cardiac disease and what is the complex underlying mechanism that links theese two conditions

PHARMACOGENETICS AND INTERACTIONS OF ANTIDEPRESSANTS IN THE TREATMENT OF CO-MORBID ILLNESS

Patients who require long-term treatment for depression have an increased risk of experiencing drug interactions since they will take medications for and/or co-morbid illness. Antidepressants can be the object of drug interactions by other substances, or they can precipitate interactions by inhibiting enzyme pathways. There is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Genetic test suitable for the routine laboratory are now available for some important metabolizing enzymes (e.g. CY2D6, CY2C19) identifying those individuals who are slow or fast metabolizers of certain drugs. Specific antidepressants differ in the interactions with CYP450 isoenzymes and in their susceptibility to drug-drug interactions. The main focus of this article is pharmacokinetic drug interactions of antidepressants. With that specific knowledge, clinicians can improve outcomes of depressed patients, by considering the possibility of drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance

PHARMACOGENETICS AND INTERACTIONS OF ANTIDEPRESSANTS IN THE TREATMENT OF CO-MORBID ILLNESS

Patients who require long-term treatment for depression have an increased risk of experiencing drug interactions since they will take medications for and/or co-morbid illness. Antidepressants can be the object of drug interactions by other substances, or they can precipitate interactions by inhibiting enzyme pathways. There is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Genetic test suitable for the routine laboratory are now available for some important metabolizing enzymes (e.g. CY2D6, CY2C19) identifying those individuals who are slow or fast metabolizers of certain drugs. Specific antidepressants differ in the interactions with CYP450 isoenzymes and in their susceptibility to drug-drug interactions. The main focus of this article is pharmacokinetic drug interactions of antidepressants. With that specific knowledge, clinicians can improve outcomes of depressed patients, by considering the possibility of drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance

THE ROLE OF CYP2D6 AND TAQI A POLYMORPHISMS IN MALIGNANT NEUROLEPTIC SYNDROME: TWO CASE REPORTS WITH THREE EPISODES

Malignant neuroleptic syndrome (MNS) is a serious and potentially fatal side-effect of neuroleptic treatment. Beside antipsychotic drugs, other psychotropic drugs such as antidepressants and lithium carbonate can cause this life threatening sideeffect. Underlying mechanism of this side-effect is still unknown and debated. So far some risk factors have been identified, with clinical observations and recent pharmacogenetic research suggesting (with inconsistent findings) correlation between genetic mechanisms and predisposition to MNS. Polymorphisms of CYP2D6 enzyme through which most psychotropic drugs are metabolized and TaqIA DRD2 which is target for antipsychotic drugs could be the link between pharmacogenetic factors and potential for development of MNS. In this paper we present two case reports with clinical presentation of three consecutive MNS. One patient developed MNS while he was taking combination of drugs: first time haloperidol, promazine and fluphenazine, second time fluphenazine and perazine and third time clozapine, promazine and valproic acid consecutively. The other patient developed MNS while taking following combination of drugs: first time haloperidol and lithium carbonate, second time risperidone and third time clozapine consecutively. Pharmacogenetic analysis for CYP2D6 and TaqI A DRD2 polymorphisms for both patients was done. Genotypisation of CYP2D6*1*3*4*5*6 in both patients showed no evidence of poor metabolizer phenotype. On the other hand, first patient was heterozygous for CYP2D6*4 (genotype *1/*4). CYP2D6 polymorphisms could have clinical significance because may lead to toxicity and unwanted side-effects in standard usual antipsychotic dose ranges. Analysis Taql A DRD2 polymorphism for first patient showed that he is heterozygous for A1 allele (genotype A1A2) which is commonly associated with predisposition to MNS. According to our literature three consecutive MNS are rarely described, and incidence of MNS generally is too low to perform clinical research. Many patophysiological mechanisms may probably underlie this complex and potentially fatal syndrome, still unknown etiology. But, genetic mechanisms could be significant. Further pharmacogenetic research, findings and analysis in patients who develop single or repeated MNS are strongly recommended. In long term, pharmacogenetic analysis, implemented in daily clinical practice, could help in prevention of this extremely serious side-effect

Antipsychotics

Antipsihotici su primarno namijenjeni liječenju shizofrenije. Međutim, primjenjuju se i u drugim poremećajima što je navedeno i u Hrvatskim smjernicama za liječenje shizofrenije. Mehanizam djelovanja antipsihotika temelji se na dopaminskoj teoriji shizofrenije tako što ublažavaju učinak dopamina na D2 receptore. Antipsihotici se razlikuju prema učinku na ostale neurotransmitorske sustave. Na taj se način ostvaruju učinci na negativne, kognitivne i depresivne simptome. Najbolji je odgovor na antipsihotik u ranoj fazi shizofrenije kako bi se spriječile kasnije komplikacije, poput učestalih hospitalizacija, terapijske rezistencije, kršenja zakona i zlouporabe supstancija. Nastavak terapije antipsihoticima u bilo kakvom obliku više sprječava relaps nego prekid terapije. Nuspojave antipsihotika ovise o njihovu mehanizmu djelovanja. Najčešće su nuspojave ekstrapiramidni sindrom, sedacija, akatizija, porast tjelesne mase, antikolinergičke nuspojave, ortostatska hipotenzija, hiperprolaktinemija i produljenje QTc intervala, no njihova pojavnost se razlikuje ovisno o vrsti antipsihotika. U članku su prikazane mogućnosti ublažavanja nuspojava antipsihotika. Pri izboru antipsihotika vodimo se simptomima koji dominiraju kliničkom slikom, podnošljivošću antipsihotika te načinom primjene.Antipsychotics are primarily used to treat schizophrenia, but are used in several other disorders as well, which is also recognized in Croatian guidelines for the treatment of schizophrenia. The antipsychotic mechanism is based on the dopamine theory of schizophrenia and moderating the effect of dopamine on D2 receptors. Antipsychotics differ according to their effect on other neurotransmitter systems. They have an effect on negative, cognitive, and depressive symptoms. In the early stages of schizophrenia, antipsychotic medication yields the best results, thus preventing subsequent complications such as frequent hospitalization, therapeutic resistance, law-breaking, and substance abuse. Continuing antipsychotic therapy in any form prevents relapse as opposed to discontinuation of therapy. Side effects of antipsychotics depend on the mechanism of action. The most common side effects are extrapyramidal symptoms, sedation, akathisia, weight gain, anticholinergic side effects, orthostatic hypotension, hyperprolactinemia, and prolongation of the QTc interval, but their prevalence differs depending on the type of antipsychotic. This article provides recommendations to diminish those side effects. When choosing an antipsychotic, we ought to be led by the symptoms that dominate the clinical picture, tolerability of the antipsychotic, and method of administration