Evidence-Based Management of Schizophrenia

Task:

Schizophrenia is a recurring and long standing mental health problem (APA,2013). According to the Wold Health Organization (WHO) in 2019, among men and women schizophrenia is one of the top causes of significant lost of years due to disability worldwide. The kind of the disability that it can cause in the life of a person is so catastrophic that it can massively impair and oppress one’s occupational, social and relational functioning for multitude of years. The Purpose of this paper is to give an overview of an actual scenario of a schizophrenic patient and discuss evidence based guidelines on its psycho pharmacologic management.

Overview of Initial Physical Clinical Assessment

Patient J.F was a 23 y/o Hispanic male patient brought in by his father due to patient patient’s refusal to eat and drink.  Patient says” I have not eaten in 16 days.” Patent’s says that he has lost a lot of weight.  He says that the food is poisoned and refuses to eat. Patient says that he hasn't been sleeping. Patient says that “Angel Gabriel is trying to kill me.” Patient very suspicious. Patient uses a pillow under his lower back while lying down. Patient complains that,” I do not know why my back is hurting.” Patient is very confused and unable to provide a lot of information as to what is happening to him and why he is in the hospital. Patient has a difficult time following conversation. Patient occasionally breathes with his tongue sticking out also while he is sleeping. Patient says his back hurts but that is all the information that he can provider. Patient states that he is homeless for the past 2 years and that his father doesn't want him anymore at the house. Patient seems to sleep with protruding tongue and heavily. Patient is disoriented and exhibiting thought blocking. Patient states that he is not willing to take medication.

Patient History

Patient has no known psychiatric history. Patient’s medical history is unremarkable with no known mental or cognitive disorder. There is no known abuse of drugs, smoking or alcohol. Patient’s mother reported a family history of schizophrenia with patient’s aunt dying of suicide after along bout of struggle with schizophrenia. Patient denies any history of arrest. Patient is single, unemployed and homeless. Patient’s mother says that patient was born full term, no complications. Patient admits to history of sexual abuse by his uncle as a child until his teenage years. Patient say that his uncle died last year. Patient says that nobody in his family knows about this sexual abuse.

Mental Status Exam (MSE)

Patient is 23 y/o male Hispanic patient, appears his stated age, dressed in hospital gown with poor grooming and hygiene.  Upon examination, patient was uncooperative, disheveled, malodorous. and moderately anxious. Patient showed very little eye contact during interview. Patient was found stuffing papers and other materials in his underwear. Patient’s showed selective mutism, non spontaneous, hypo verbal, rate speech slowed and disorganized. Patient described his mood as “I am alright.” His mood was sluggish, labile and incongruent His affect was blunted and flat. Patient’s thought process was linear with thought blocking. His thought content was stable, with no thoughts of harming self or others.  Patient admits to hearing voices. He said that he can to angles but that he says that “Angel Gabriel is out to get him”.  Patient denies visual, tactile or olfactory hallucination. Patient has poor insight into his condition and poor judgment. Patient was disoriented, had poor concentration, sleepy, drowsy, lethargic, stuporous Patient spends most of his time in his bed showing lack of motivation. He isolated withdrawn, refuses to participate in group meetings. Pt has refused  his medicines and showed negativisim. Patient responds to internal stimuli. Interview Questions Questions that would help guide in the diagnosis of schizophrenia are as follows. How can I help you today? What is reason why you are here today? Are you hearing voices? Are you seeing things that are not really there? Do you have thoughts of hurting yourself or other people? How is your sleep? What is your eating habit? Have you ever been treated for a mental disorder, either as outpatient or inpatient? If yes, where, when and what pharmacologic and therapy was used? What medications have you taken in the past? If yes, ask for name and dose and if there is non compliance? Have you ever used recreational drugs, alcohol or smoking? If yes, what, how much, when last taken? Any past medical, surgical history, allergy history? History of head injury? Ask about social status, occupation and job history, living situations and relationships, education history. Ask about family medical and psychiatric history. Ask about stress overcome in the past, coping mechanism, personal strengths, best period of one’s life and current stressors. Diagnosis of Schizophrenia According to the American Psychiatric Association (APA, 2013), the diagnostic criteria for schizophrenia are the following: at least 2 of the following symptoms of psychosis have been present over a month delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms of avolition, alogia, anhedonia or blunted affect. In the scenario pointed here, pt had hallucinations, disorganized speech, disorganized behavior and negative symptoms. In the patient scenario, patient had been exhibiting auditory hallucinations of angels talking to him, along disorganized speech, disorganized behavior and negative symptoms of blunted affect, avolition and alogia. He has been showing signs of psychosis for more than six months. All the labs done were esentially within normal limits, with drug screen, alcohol scree, serology studies also essentially negative. Stage I Initial Visit: Monotherapy The first line management of schizophrenia are anti psychotic medications (Stahl, 2014). In clinical trials, the anti psychotic medications have been found to be very efficient in managing the behaviors and symptoms associated with this mental disorder. However, anti psychotics can have disabling side effects. Essentially, a careful and continuous assessment and management of these side effects and adverse reasons are a core aspect of the management of this mental illness. Both evidenced-based psycho pharmacotherapy and psycho social therapy are fundamental in the goal directed plan towards patient’s recovery. The management of schizophrenia is dependent on the various phases of this illness. In the acute phase, a patient may come in due to a psychotic relapse or a first psychiatric episode (Sadock, Sadock, & Ruiz, 2015)   Necessary Labs and Test In the patient scenario, that patient came in with a psychosis for the very first time. This is initial assessment but to the present psychosis, the focal point of consideration is directed at reducing the gravity of psychosis, disorganized thoughts and disorganized behavior. Incumbent with this assessment, the pre treatment vitals of knowing the patient’s waist circumference, body mass index (BMI), blood pressure, heart rate and the presence of any movement disorder need to part of the baseline neurological and physical examination. Along with this baseline assessment, laboratory evaluations needs to be started prior to the commencement of an anti psychotic drug management (Sadock et al.,2015). Typically, anti psychotic can be started even when the laboratory results are not in yet. Clozapine is an exemption to this rule as laboratory tests need to be resulted prior to starting its regimen (Uptodate,2019). Laboratory profile includes thyroid function, renal, liver, lipid, fasting glucose, electrolytes. Symptoms of metabolic syndrome should be carefully monitored. In the case of clozapine, the white blood count (WBC) differential needs to be checked. Patients with known cardiac problem, need to have a baseline electrocardiogram (ECG) on board prior to starting anti psychotic medications. In addition, when starting anti psychotic medications that can potentially cause prolongation of QT as in the case of ziprasidone, clozapine, thioridazine and iloperidone, ECG needs to be done prior to treatment (Uptodate, 2019). According to Uptodate (2019), research trials have seen the impact of anti psychotics in alleviating the positive symptoms schizophrenia inclusive of delusions, hallucinations and suspiciousness. Comparatively, an anti psychotics drug versus other anti psychotic counterparts have not shown any convincing argument to predict that one anti psychotic is better than another in the management of this disorder’s positive symptoms (Uptodate, 2019). Clozapine is an exemption to this rule as this drug has shown to be effective in managing patient’s who have not fully responded to other anti psychotic regimens (Sadock et al., 2015). However, due to the risk of agranulocyotosis when treated with clozapine, this drug is preferably used for patients either intolerant to other anti psychotics or have not responded fully to anti psychotics. Symptoms of avolition- apathy, affective flattening, alogia are negative symptom schizophrenia. Negative symptoms are hard to treat. However, in a meta analysis trial in 2015, it has shown a small but statistically essential reduction in negative symptoms when treated with second generation antipsychotics versus first generation antipsychotics (Uptodate, 2019). Choosing which antipsychotic would fit patient profile can be arduous. It is important to note, that despite the variations in the efficacy of anti psychotics, knowledge about side effects and formulations are vital consideration with anti psychotic selection (Stahl, 2014). In addition to this, patient profile which considers whether patient is on first psychotic episode, whether patient is a partial responder to anti psychotic, patient agitation, patient sensitivity to side effects such as sedation, hypotension, weight gain, extrapyramidal (EPS) symptoms, are all part of the continuum of considerations with anti psychotic selection (Sadock et al.,2015). Anti psychotics are divided into conventional or first generation antipsychotic and the second generation anti psychotics.  The advantage of newer second generation anti psychotics is that they seemingly cause less EPS symptoms versus the first generation anti psychotics, especially when high dosages are used (Stahl, 2014). Choosing Risperidone. Risperidone was chosen since this is a second generation antipsychotic with less risk for EPS symptoms and tardive dyskinesia. In addition, if a patient becomes non compliant, this drug has its LAI form. This drug is able to target both positive and negative symptoms, cognitive functioning, unstable mood and aggression (Stahl, 2014). In the patient scenario, the patient was started on risperidone 1 mg once a day at night.  The patient was carefully watch for several days for any side effects. The patient showed tolerance to riperidone as she showed minimal sedation, no hypotension and no akathesia. According to Stahl (2014),when a patient with schizophrenia is started on antipsychotics, it is vital to educate the patient that initial response side effects of postural hypotension, sedation and restlessness are common. This type of education is important to veer away from patient misconception that he is worsening with the drug of choice. The rate of improvement of a patient is usually faster during the first  two weeks, with continuation of improvement during the next weeks to months that follow (Uptodate, 2019). The titration of most anti psychotics from the initial dosage to the therapeutic range is dependent on patient’s tolerance and the patient’s sensitivity to tolerate the potential side effects of sedation and hypotension (Stahl, 2014). Moreover, the exact time frame of titration varies from drug to drug. Clozapine and Quetiapine titration is should be gradual before attaining the therapeutic range. Typically, the titration for quetiapine  can be reached in 5-6 days versus clozapine which can range from 2-3 weeks for therapeutic range (Uptodate,2019). Generally, it can take days to as much as 4-6 weeks for the resolution of psychosis (Sadock, 2015). In this context, it is pertinent for clinician to resist that impulse to change the antipsychotic drug or up the dosage prematurely. Once the therapeutic range is reached, it is vital to wait for at least several days to observe if the patient is showing scarce to no improvement at all. Dosing at a higher end is controversial as it is crucial to be cognizant of emergence of drug side effects. If the dose used is above therapeutic range, and the patient is not visibly presenting any improvement, then the dose should be reduced (Uptodate, 2019). Dosing, Titration, Duration and Side Effects of Risperidone The approved dosing for risperidone is sixteen mg/day according to the Food and Drug Administration (FDA)(2019). However, recent research studies hae instigated that six to eight mg/day, which is drastically lower than what is FDA approved maximum dose, is the typical maximum dose for risperidone to optimally reach its effectivity (Uptodate, 2019). As mentioned above in the patient scenario, the initial  starting dose for risperidone was 1 mg once a day at night (Stahl, 2014). Since patient showed tolerance to the initial dosage, the dose was increased to risperidone 1.5 mg on the second day. With continued tolerance, risperidone was increased daily by 0.5 mg until four mg is reached, which is the typical therapeutic dose for most patients (Uptodate, 2019). Patient was continued on this dose for an additional two weeks. The patient showed minimal improvement with the succeeding weeks and titration was slowly increased every week by 1 mg until six mg/day was achieved, closely observing for signs of improvement and any untoward reactions. Risk for EPS may be observed with risperidone dose of more than eight mg/day. Due to the dose related toxicities associated with antipsychotics, it is prudent to use the lowest dose of effectively for patients (Sadock, 2015). The essential premise to note is that higher dosages are closely linked to toxicities (Stahl,2014). Consequently, increasing the dose in a patient that who may already be experience EPS symptoms may not be beneficial as symptom reduction in this instance would be unlikely. Typically in the first weeks following initiation of treatment, patients show a decrease in the severity of their symptoms in the first weeks, symptoms of hallucinations and delusions become less frightening with reductions of lingering delusions (Uptodate, 2019). According to Stahl (2014), the potential side effects of risperidone are diabetes, dayslipidemia, EPS, hyperprolactinemia, dizziness, insomnia, sedation, tradeoff dyskinesia, sexual dysfunction, orthostatic hypotension, weight gain, nausea and constipation. In this case, getting prolactin levels after several days of drug administration may be prudent (Stalh,2014).   Stage 2: Non-Responder to Stage 1: Titration up The patient in the case scenario was carefully observed on a stable dose of risperidone six mg for two to six weeks. The patient showed minimal response during the above mentioned time period. Recent studies indicate that a patient who has shown minimal improvement in two weeks , will unlikely show any robust change in the succeeding weeks.  According to the schizophrenia PORT recommendations in 2009, antipsychotic medication trial ought to last for two to six weeks (Kreyenbuhl et al,2010). Quetiapine on the other hand would require a slower titration. Hence, a longer trial period (Uptodate, 2019). In the case of non responders or partial responders to treatment, the anti psychotic dose can be increased towards the recommended high end dosage of FDA. This is controversial as most studies have shown that doses above the recommended range have not significantly showed greater effectivity. Trials of high doses, if tried should be done at a short limited time frame, with a projected three month reassessment. Without clear evidence of improvement, high doses should not be continued (Uptodate, 2019). In this scenario, the patient showed partial response to treatment in the six weeks span.The risperidone was slowly increased every week by one mg until eight mg was reached. With risperidone of 8 mg, patient became too sedated, was showing restlessness, akathisia, and abnormal facial twitches. In the presence of side effects and only partial response to risperidone, patient dosage was titrated back to risperideon 6 mg/day. Stage 3: Non-Responder to Stage 2: Changing Antipsychotic In the case of poor response due to side effects, switching to antipsychotic may be beneficial. In the case of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial (Bellavia et al., 2019), patients who have gained during the antipsychotic regimen, evidently lost weight when changed to zipsidone. However, most trials have indicated that if a patient is a poor responder to one antipsychotic, then it is most likely that this patient would be a poor responder to the another antipsychotic, except when the antipsychotic is clozapine. Moreover, the CATIE trial depicted that patients who were on risperidone or olanzapine, had better improvement when randomly assigned to continue to same antipsychotic drug  versus changing antipychotic (Bellavia et al., 2019). According to Uptodate (2019), there are two basic strategies of switching antipsychotics. The first one is cross tapering where the current drug is simultaneously tapered  in 1-2 weeks, while the replacement drug titrated in 3-4 steps in a span of days to several weeks. However, for patients who have a higher risk for relapse, the current drug may be continued at his full dose, while the new antipsychotic is slowly tapered up until its therapeutic range (Uptodate,2019). Once the new drug has reached its target range, then the old drug can be slowly weaned down in 1-2 weeks. Gradual tapering is recommended for all antipsychotics. This is especially true when tapering clozapine as abrupt withdrawal can cause emergency of cholinergic rebound and abnormal movement disorders.The addition of another antipsychotic is of little empirical evidence in clinical practice (Uptodate, 2019). Choosing Olanzapine Olanzapine, a second generation antipsychotic like risperidone was chosen due to less risk for EPS symptoms. This drug side effect profile of weight gain and sedation may help address patient’s recent loss of weight and lack of sleep. This drug is able to address both positive and negative symptoms, cognitive and aggression symptoms. If patient becomes non compliant, patient has LAI form. Dosing, Titration, Duration and Side Effects of Olanzapine   In the patient scenario, resperidone was cross tapered to olanzapine in a span of 2 weeks. Because of the potential for weight gain and metabolic side effects,  olanzapine is typically not used as the initial monotherapy. Olanzapine ought to be considered with patients with poor response to the first line antipsychotic agent. Olanzapine was started at an initial starting dose 5 mg oral per day. According to Schizophrenia PORT (Kreyenbuhl et al., 2010), patients who have first episode psychosis should received a antipsychotic starting dose in the lower half of the recommended dose. Olanzapine dose increased by 1.25 mg per day until 10 mg is reached, while risperidone dose was downgraded by 1 mg per day in a span of 1-2 weeks (Stalh, 2014). Again, carefully watching patient improvement, side effects and withdrawal symptoms are pertinent during this cross tapering. Patient was maintained at olanzapine dose of 10 mg for eight weeks. According to Stalh (2014), the potential side effects of olanzapine range from sedation, depression, fatigue, ataxia, slurred speech, weakness, forgetfulness, confusion, hallucations, hypotension, mania, hyper salivation, respiratory depression,  hepatic and liver dysfunction, weight gain, and seizures.   Augment with Divalproex, dose, side effects According to Stahl (2014), if all monotherapy fail, the adjunct of a mood stabilizer may be administered. In the patient scenario, patient was started on divalproex immediate release of 500 mg oral twice day was started. Patients trough plasma level was checked on the fourth day. Patient showed trough levels of 89 ug.ml. Patient was maintained on 500 mg PO BID (Stahl, 2014). Valproate levels, once therapeutic range is achieved , may be checked once a month. More frequent monitoring may be followed with every dosage change.  No untoward reactions were observed. Patient’s typically tolerate trough levels of 100 ug/ml. The possible side effects from divalproex aresedation, tremor, dizziness, ataxia, headache, asthenia, abdominal pain, weight gain, polycystic ovaries, hyperandrogenism, hyperinsulinemia, decreased bone mass,, hepatotoxicity, tachycardia or bardycardia, drug reaction with Eosinophilia (DRESS), weight gain or lipid dysregulation (Stalh, 2014). With the advent of the drug combination of olanzapine and divalproex, patient showed only partial response .  

       Stage 4: Non-Responder to Stage 3 : Treatment Resistant Schizophrenia

Factors that Influence the Medications

Schizophrenic patients who respond poorly to an initial antipsychotic, despite dose adjustments and changing mono therapy, with at least two antipsychotic trials of more than six weeks at maximally tolerated doses, are categorized as having treatment resistant schizophrenia (Sadock, 2015). It is vital to note that prior to classifying patient’s schizophrenia as refractory, the patient’s current management and psychosocial interventions such as cognitive behavioral therapy CBT), should be fully optimized (Sadock, 2015). Moreover, causes for pseudo resistance such as medication non adherence should be carefully assessed, reevaluation of primary diagnosis, consideration for co occurring conditions such as mental disorders and substance abuse, medical conditions such as obesity and possible sleep apnea, triggers and stressors, antipsychotic drug side effects,  are all factors that need to be closely looked into when considering refractory illness (Uptodate, 2019).

Choosing Clozapine Patient who’s psychosis do not significantly improve after two mono therapy trials , ought to be put on clozapine trial prior to a trial of an antipsychotic dual therapy (Sadock, 2015). According to Uptodate, 2019, the Treatment Response and Resistance in Psychosis Working group (TRRIPE), established the minimal criteria for treatment resistant schizophrenia includes diagnosis of schizophrenia, at least moderate symptom severity, functional impairment,  and at least 2 mono therapy trials of > 6 weeks. Optimal criteria for TRRIP includes one out of two antipsychotic trial should include one LAI (Uptodate, 2019). The eligibility criteria for clozapine includes absolute neutrophil count of greater than 1500 cells/mL, benefits weight more than risks, ability for treatment monitoring. If clozapine is tolerated and without adverse reactions, clozapine trial should be tried for at least twenty four weeks. The decision to continue clozapine ought to be based patient satisfaction, an improvement on patient’s well being and functionality. These benefits need to be clearly upfront to justify the use of this medicine (Uptodate, 2019).  Clozapine is favorably more effective than other anti psychotic but due to its risk if agranulocytosis, is reserved for refractory schizophrenia.

Titration, Duration and Side effects of Clozapine

Neuropenia, clozapine induced myocarditis, seizures are contraindicated in using clozapine (Stalh, 2014). Other potential side effects to clozapine include tardive dyskinesia, dyslipedemia, hyperglycemia, tachycardia, weight gain, sailorhea and orthostasis (Stalh, 2014).  

According to Clozapine REMS in 2019, registration for Risk Evaluation and Mitigation Strategy (REMS) program, clinicians enlist patient’s name and must undergo monitoring when on clozapine. Routine monitoring of neutrophil count is weekly for the first 6 months, e