Pharmacotherapy In Refractory Schizophrenia

Pharmacotherapy in refractory schizophrenia

Strength or treatment tolerance is a great therapeutic challenge, it is estimated that of patients in treatment of 20 to 30% do not respond properly to therapy. Therefore, the evaluation of other therapeutic options is necessary. Schizophrenia is considered to be refractory when there is no response to at least two antipsychotics with different mechanism of action, including at least one of the second generation, in the relevant doses and for a duration of a period of 2 to 8 weeks in which nosignificant relief of symptoms is evidenced., mainly of the positive signs of the disease.

In case of suspecting a resistance to antipsychotic therapy it is important to consider:

• Reevaluation of the diagnosis of a schizophrenic disorder: evaluate and rule out if necessary personality disorders particularly severe, mania or depressive disorder, also brain tumors and encephalopathies can cause psychotic states. In addition to considering comorbidities such as affective or obsessive disorders compulsive.
• Possible denial of the patient with respect to medication intake: breach or lack of adhesion may be the reason for the failure to respond to antipsychotic therapy.
• Antipsychotic dose and treatment duration: verify that they are recommended and suitable for the patient. A minimum period of between 2 to 8 weeks is recommended. Several studies show that the antipsychotic effect of drugs can be evidenced within the first 2 weeks of treatment, even after the first 24 hours after the administration of the medication.

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• Possible masking of the response to therapy for the side effects produced by antipsychotics: expected adverse events such as acatism can be confused as mental agitation can be misunderstood.
• Monitoring of drug concentrations: although a clear relationship between the plasma concentration of antipsychotics with their response has not yet been stipulated, these values can be useful to support therapeutic failure
• Genetic polymorphism: in cytochrome P450, which is the enzyme responsible for the metabolization of most psychotropic drugs, there may be an increase in enzymatic activity or a reduction
• Possible medication interactions: They should be considered in case of combined therapies and in polymedicated patients. Smoking is clinically relevant, because tobacco can increase the clearance of medications such as clozapine and wave.

In case it is not established that there is definitely no response to the initial treatment the most used strategies are: the increase in dose of the antipsychotic drug currently administered or the change to a new drug. Dose increases above the approved range are not recommended by the guides of international psychiatric society as a treatment option for the management of refractory schizophrenia.

• Dose increase: with respect to first-generation antipsychotics it is concluded that daily doses greater than 800-1000 mg equivalent chlorpromazine do not improve efficacy and are associated with an increase in adverse events, mainly extrapyramidal effects. However, the use of high doses with blood monitoring of plasma levels in patients with polymorphisms of CYP450 can be beneficial.
• Drug change: the change from one medicine to another, each in monotherapy, is the strategy currently most used in case there is no response.

In a double -blind study carried out with patients refractory to an initial monotherapy of 2 weeks with risperidone, a group was left with the same dose of risperidone (2 to 6 mg /day, n = 192) and the other changed to Olanzapina (10-20 mg / day, n = 186), after treatment for 10 weeks a small significant advantage was found in favor of the change to Olanzapina. In another randomized study analyzed with 21 refractory patients, 4 weeks of 20 mg / day flufenazine monotherapy were administered and the following change were made by making 3 study groups: continuation of the medication with flufenazine at the same dose, increased dose to flufenazine to80 mg / day and change to haloperidol 20 mg / day. The results were not conclusive, because there is not enough evidence for clear therapeutic recommendations regarding a change strategy. Even if only moderate to low response rates can be expected, some patients seem to benefit from a change of medication.

It should be considered that there are patients who can benefit from a high dose medication. So it is important to evaluate and take into account the patient’s medical history for a drug change. The gradual reduction of the dose of the first drug is recommended, while simultaneously the dose of the second fits the maintenance dose. Alternatively, the dose of the first antipsychotic can be kept at the same dose while the dose of the second compound gradually increases to a therapeutic level and only until that moment the dose of the first agent will reduce.

Taking into account pharmacodynamic considerations in the change of drug. For example, in a clinical trial, it was evidenced that patients refractory to perfenazine treatment benefit significantly more than a change to wave or quetiapine compared to risperidone.

An overview of the pharmacological treatment available for refractory schizophrenia is mainly given by several clinical trials that stipulate that clozapine is characterized by high verified efficacy in these patients, and therefore is classified as first -line treatment in schizophrenia resistant totherapy. In an essay it was corroborated that only clozapine is significantly more effective than first generation antipsychotic drugs. However, due to its benefit risk, clozapine can be used only after at least two failed attempts of previous treatment with two different antipsychotics in appropriate doses and periods of time. Its adverse events, mainly sedation, weight gain and hypersalivation can hinder the fulfillment of patients.

In case of not tolerate the treatment with clozapine or its administration is not feasible to the patient some guides refer to treatment preferably with wave or risperidone. In clinical trials of resistant patients these drugs in combination were not significantly lower than standard treatment with clozapine. The use of combined therapy is widely used in the clinical field but has not demonstrated significant advantage over treatment in monotherapy.

Currently, clozapine is the most evaluated antipsychotic drug in relation to combined treatments. The most frequently investigated simple combination is clozapine and risperidone. From the pharmacological point of view, it seems favorable combining antipsychotic agents with low -dopaminergic properties, such as clozapine, with antipsychotics that are characterized by particularly strong affinity with dopamine receptors according to some studies it seems that aripiprazole treatment can reduce the effectsAdverse metabolic induced by antipsychotics and high levels of serum prolactin. In combined therapy, efficacy, interactions and adverse effects should be controlled closely, since the risk of metabolic side effects and interruption by all causes can increase significantly by the administration of combinations, and in case there is noTreatment response will be necessary to consider monotherapy again.

Antipsychotics remain the most effective pharmacological treatment approach to schizophrenia, however the current treatments of these disorders are mainly symptomatic and inappropriate, and are often associated with a series of unwanted side effects not desired by this new investigations seek and propose new possible formsof treatment, for example therapies directed to the immune system, diets rich in polyunsaturated fatty acids, uses of cannabinoids, among others.

In a study through exploration of positron emission tomography, neurophysiopathology of resistance to antipsychotic therapy through the comparison of patients who do not respond to people who respond to therapy, it was determined that the ability to synthesize dopamine wasminor in patients with treatment resistant to treatment than in those who respond to conventional therapy. This suggests that a drug that achieves a blockade of dopamine receptors can be especially effective in the treatment of refractory patients with high dopamine synthesis capacity.

Adenosine is a homeostatic bioenergetic network modulator that is capable of affecting synergily complex networks at different levels . By affecting dopamine and glutamate activities in the brain it is presented as a promising candidate to reverse the functional imbalance in these neurotransmitter systems, it is believed that it is the basis of the genesis of the symptoms of schizophrenia. The adenosine hypothesis of schizophrenia suggests that adenosybinal dysfunction could contribute to the appearance of multiple neurotransmitter dysfunctions and because of its importance in early brain development and regulation of the immune response of the brain, it also has a direct relevance for the etiology of schizophrenia. But the pharmacotherapy of schizophrenia based on the hypothesis of dopamine remains unsatisfactory for the negative and cognitive symptoms of the disease, for example the A2AR agonists can be valuable due to their antipsychotic potential, but the systemic use of A2ar agonistsIt could be associated with deterioration in cognitive performance and peripheral side effects. Therefore, individual adenosine receptors most likely do not represent adequate pharmacological objectives for the treatment of schizophrenia.

The evidence suggests a role of 5-hydroxytriptamine receptors (5-HT; serotonin) -1a in the modulation of the neurotransmission of dopamine and in the improvement of pharmacotherapy in schizophrenia and Parkinson’s disease. The current state of knowledge suggests that medications simultaneously directed to dopamine and 5-HT1A receptors can improve pharmacotherapy for schizophrenia and Parkinson’s disease. The activation of 5-HT1A somatodendritic receptors in the nucleus of the dorsal RAFE has an important role in the relief of extrapyramidal symptoms and induced levodop-induced dyskinesia induced by antipsychotic treatment. The drugs that act exclusively through Dopamine and 5-HT1A receptors are very necessary to validate the potential role of 5-HT1A receptors in improving therapy for Parkinson’s disease and schizophrenia. The targeting of treatment lines for select brain areas could become a need to avoid the effects throughout the brain, given the generalization peripheral and central side effects of the systemic use of drugs that affect the signaling of adenosine and are the new challenge in thiscountryside.

It has been proposed that fish oils and other essential fatty acids improve the symptoms of schizophrenia or the adverse effects of medications used to treat it. Fatty acids perform critical papers in cell membranes of neurons, and certain polyunsaturated essential fatty acids, such as omega-3 docosahexaic acid, omega-6 linoleic and araquidonic acids, they seem to have abnormally low levels in the brains of patients with patients withschizophrenia. The attempt to improve endogenous levels seems to be a rational and valuable objective at the clinical level because the evidence that supplements improve the symptoms of schizophrenia is limited, however they are included in current regimes with the hope of better symptomatic control inschizophrenia.

Immunomodulating pharmacotherapy highlights the need to consider differences in basal inflammatory markers, as well as in the stage of the disease and severity of clinical symptoms, the importance of conducting longitudinal studies in individuals with schizophrenia is highlighted to determine the nature by which the activityImmune changes with activity of clinical symptoms and treatment. While there are clearly peripheral and central immune alterations in schizophrenia, the field would benefit from a better understanding of the contribution of specific cell types and phenotypes, allowing new therapeutic objectives promoted by theory. On the periphery, for example, cd14 + monocytes are key. The findings are not conclusive by heterogeneous glial cell phenotypes and small sample size. The identification of these types of protein targets could support the use of small molecules pharmacology that limits antibody -induced damage.

Finally, it is emphasized that the concomitant treatment of an antipsychotic drug with an antidepressant, mood or benzodiazepine stabilizer has not demonstrated convincing efficacy in the treatment of schizophrenia symptoms. Therefore there is not enough evidence to recommend the concomitant use of these drugs, however several guides recommend for the specific treatment of symptoms such as agitation (benzodiazepines) and antidepressants in case of depressive comorbidity.