Prognostic factors in schizophrenia Poor prognostic indicators include : Poor premorbid adjustment. Insidious onset. Onset in childhood or adolescence. Cognitive impairment. Enlarged ventricles. Symptoms fulfilling multiple criteria in DSM-IV-TR for diagnosis. Good prognostic factors include: Marked mood disturbance, especially elation, during initial presentation. Family history of affective disorder. Female sex. Living in a developing country.
Clinical management of schizophrenia The APA guidelines Treatment Recommendations for Patients with Schizophrenia divide the treatment of schizophrenia into three treatment phases: Acute Phase (initial presentation). (4 to 8 weeks) Stabilization Phase (early symptom remission). (may last as long as 6 months ) Stable Phase (maintenance treatment).
Acute Phase
Initial psychiatric assessment The goals of acute phase treatment are To ensure patient safety, To perform a comprehensive physical and psychiatric assessment To provide prompt treatment of psychotic symptoms, and To establish a therapeutic alliance with the patient and the patient's family. Acute phase treatment may involve psychiatric hospitalization if patient safety or compliance cannot be ensured in a less restrictive setting .
Physical assessment and evaluation of general medical health Vital signs and body weight (including waist circumference). Identification of substance intoxication/withdrawal syndromes including urine or serum toxicology screen. Pregnancy test for women of childbearing age. ECG (and documentation of pretreatment QTc ). CBC, electrolytes, liver function testing, metabolic panel. Brain imaging for first break (MRI preferred over CT), in the setting of focal neurologic signs or atypical presentations. EEG if symptoms suggest seizure activity.
Psychiatric assessment Safety assessment Imminent danger to self or others may require acute hospitalization. Specifically, we should elicit and document: — History or presence of suicide attempt or suicidal ideation (including means and intensity.) — Prominent mood symptoms. — Command hallucinations, hopelessness, anxiety, EPS, substance use disorders. — History of aggression or violence during current or past psychotic episodes. — Whenever possible elicit information from collateral informants
Environmental Adaptations Establish rapport with the patient, minimize the use of multiple interviewers whenever possible. If possible, perform the assessment in a structured, simple environment with minimal extraneous noise and stimuli. Employ clear, simple communication. Employ restraints only when necessary to prevent aggressive behavior toward self and others. With acutely agitated patients, assessments should be conducted with the interviewer closest to the door (for interviewer safety).
Pharmacotherapy Management of acute psychosis in schizophrenia will almost always involve the use of an antipsychotic agent. Frequently, treatment augmentation with benzodiazepines can be helpful in controlling severely distressed patients. If possible, administration of any medication should follow a doctor-patient discussion of the risks, benefits, and alternative treatments. Whenever possible, a baseline laboratory evaluation should be completed prior to the initiation of pharmacotherapy, or as soon as possible thereafter.
Antipsychotic medications choice First-generation drugs may be slightly less efficacious than some SGAs. FGAs should probably be reserved for second-line use because of the possibility of poorer outcome compared with FGAs and the higher risk of movement disorder, particularly tardive dyskinesia . Choice is based largely on comparative adverse effect profile and relative toxicity. Patients seem able to make informed choices based on these factors.
Antipsychotic medications choice Where there is prior treatment failure (but not confirmed treatment refractoriness) olanzapine or risperidone may be better options than quetiapine . Because of the wealth of evidence suggesting its slight superiority over other antipsychotics, olanzapine should always be tried before clozapine unless contraindicated. Where there is confirmed treatment resistance (failure to respond to at least two antipsychotics) evidence supporting the use of clozapine (and only clozapine ) is overwhelming.
Treatment of first-episode schizophrenia.
Treatment of relapse or acute exacerbation of schizophrenia (full adherence to medication confirmed)
Treatment of relapse or acute exacerbation of schizophrenia (poor compliance)
Goal of pharmacotherapy To optimize therapeutic benefit while minimizing side-effects. Educate patients about common side-effects of Antipsychotics to improve the reporting of short-term side-effects. Side-effects such as nausea, sedation, dystonias , and postural hypotension may be more likely to resolve early in treatment, while EPS and akathisia are more likely to persist.
Emergent pharmacotherapy in the acute phase Although oral administration is optimal to minimize patient distress, intramuscular agents may be necessary to reduce acute agitation and psychosis in patients who are unable or unwilling to comply with oral medication. Commonly used agents include: Olanzapine 5-10mg IM or Ziprasidone 20mg IM. Haloperidol 5-10mg IM (consider with benztropine 1-2mg IM to reduce risk of EPS or acute dystonic reaction). If the patient is willing to take oral medication, but adherence is in question, use of orally disintegrating tablets (risperidone ; olanzapine ) or liquid (risperidone, aripiprazole) is recommended.
Adjunctive medications in the treatment of acute psychosis Benzodiazepines – While benzodiazepines are not indicated as monotherapy in schizophrenia, they are commonly used in conjunction with an antipsychotic in the treatment of acute anxiety, agitation, or catatonia. Benzodiazepines may be administered in oral and parenteral form. Lorazepam 1-2mg IM/ po /IV for acute distress or agitation. Diazepam 5-10mg IM/ po .
Use of ECT in acute phase ECT in combination with antipsychotic medications may be considered for patients with schizophrenia or schizoaffective disorder with severe psychotic symptoms that have not responded to treatment with antipsychotic agents. The greatest therapeutic benefits appear to occur when ECT is administered concomitantly with antipsychotic medications. A trial of clozapine will generally be indicated before acute treatment with ECT. ECT may also be beneficial if comorbid depressive symptoms are resistant to treat or if features such as suicidal ideation and behaviors.
Stabilization phase During the stabilization phase, the patient's psychotic symptoms are in early remission or substantially reduced.
Goal of Stabilization phase Sustained symptom remission. Adherence to medication and therapy appointments. Minimization of stress. Successful transition and continued support in the community. Establishment of a long-term treatment plan. Medication doses that resulted in acute symptom remission should be sustained for at least six months unless they are intolerable. At each appointment, body weight, waist circumference, pulse, and blood pressure should be recorded to screen for early signs of metabolic syndrome.
Goal of Stabilization phase Monitor for common side-effects (EPS, sedation). Educate patient and family about the illness and contributing factors to relapse, including medication nonadherence and substance use. If possible, and with the patient's consent, identify one or more community informants that can contact the treatment team if signs of psychosis reemerge. Educate and engage patient in symptom monitoring. Arrange follow-up with outpatient mental health providers prior to hospital discharge.
Stable phase
Stable phase During the stable phase of illness, the goals of treatment are to manage medication side-effects, to monitor medication adherence, and to teach the patient to engage in psychiatric self-monitoring. Furthermore, the focus of care includes general medical care, the involvement of family and other community supports, and the identification and reduction of factors likely to contribute to relapse. The goals of stable phase treatment are continued symptom remission, prevention of psychotic relapse, social rehabilitation, and improvement in overall QOL.
Reduction of relapse risk The importance of continuing medications even after symptom remission has been well established. APA treatment guidelines and Maudsley Prescribing Guidelines recommend that first-episode patients continue maintenance antipsychotics for no less than one to two years following their psychotic episode. Studies in first-episode patients have found that discontinuing antipsychotics increases the risk of relapse five-fold.
Reduction of relapse risk It is vital that patients, carers and key workers are aware of the early signs of relapse and how to access help. Antipsychotics should not be considered the only intervention. Psychosocial and psychological interventions are clearly also important. Patients with recurrent episodes should be maintained on medications for a minimum of five years of stability before a discontinuation trial is considered. Patients with recurrent, severe psychotic episodes (severe functional impairment, violent behavior) should be maintained indefinitely.
Reduction of relapse risk Suicide risk (10%) is also concentrated in the first decade of illness. Antipsychotic drugs, when taken regularly, protect against relapse in the short, medium and long term. Those who receive targeted antipsychotics (i.e. only when symptoms re-emerge) have a worse outcome than those who receive prophylactic antipsychotics. Depot preparations may have an advantage over oral in maintenance treatment, most likely because of guaranteed medication delivery.
Reduction of relapse risk Meta-analysis of clinical trials has shown that the relative and absolute risks of relapse with depot maintenance treatment were 10to30% lower than with oral treatment. Meta-analysis of data for 2032 patients concluded that the risk of relapse with SGAs is less than that associated with FGAs. Not only does non-adherence increase the risk of relapse, it may also increase the severity of relapse and the duration of hospitalisation . The risk of suicide attempts also increases four-fold. Amongst people with schizophrenia, non-adherence with antipsychotic treatment is high; only 10 days after discharge from hospital, up to 25% are partially or non-adherent, rising to 50% at 1 year and 75% at 2 years.
Negative symptoms in schizophrenia Psychotic illness should be identified and treated as early as possible as this may offer some protection against the development of negative symptoms. For any given patient, the antipsychotic that gives the best balance between overall efficacy and side-effects should be used. Meta-analyses have shown no significant advantages of SGAs over haloperidol in reduction of negative symptoms. However, until this issue is decided by adequate controlled studies, it is probably reasonable for clinicians to consider changing to an SGA for patients with substantial negative symptoms in an attempt to minimize any that are secondary to EPS.
Negative symptoms in schizophrenia Ensure EPS (specifically bradykinesia ) and depression are detected and treated if present, and consider the contribution of the environment to negative symptoms (e.g. institutionalisation , lack of stimulation) Consider augmentation of antipsychotic treatment with an antidepressant such as an SSRI, ensuring that choice is based on minimising the potential for compounding side-effects through pharmacokinetic or pharmacodynamic drug interactions If clozapine is prescribed, consider augmenting with lamotrigine or a suitable second antipsychotic. There are insufficient data to make recommendations about other pharmacological strategies, but pregnenolone , minocycline , selegiline , Gingko biloba , testosterone and ondansetron may have potential.
Catatonic symptoms in schizophrenia Approximately 80% of catatonic patients will respond to benzodiazepine treatment and response is usually seen within 3–7 days. Patients with schizophrenia are somewhat less likely to respond to benzodiazepines, with response in the range of 40–50%. If catatonic symptoms do not resolve rapidly with lorazepam , ECT treatment is indicated. The response of catatonic symptoms to ECT is about 85% but may be lower in patients with schizophrenia than in patients with mood disorders. The use of antipsychotics in patients with catatonic symptoms is controversial. During the acute phase of catatonia, the use of an antipsychotic should be avoided, more so in cases of malignant catatonia where their use may be catastrophically harmful.
Algorithm for treating catatonia.
Treatment of Schizophrenia in Pregnancy and lactation. Risks of various psychotropic medications to the fetus, newborn, and breast-fed infant. There are substantial data on fetal exposure to first-generation antipsychotic medications, with relatively little evidence of harmful effects, especially with high-potency agents in newborn, and breast-fed infant. Much less information is available regarding fetal exposure to second-generation antipsychotic medications. Most antipsychotics are rated FDA Pregnancy Category C.
Class and drug name Dosage range Approximate oral dose Equilvalants Parenteral dosage (mg) t1/2 Butyrophenone Haloperidol 5-30 2 5-10 21 Haloperidol decanoate NA NA 25–100 every 1–4 weeks Dibenzoxazepine Loxapine succinate 40-100 15 25 Diphenylbutylpiperidine Pimozide 2-6 1 NA Dihydroindolone Molindone hydrochloride 50-225 10 NA
Class and drug name Dosage range Approximate oral dose Equilants Parenteral dosage T1/2 Phenothiazines Chlorpromazine 200-800 100 25-50 6 Thioridazine 150-800 100 NA Mesoridazine 75-300 50 25 Trifluoperazine 5-20 5 1-2 Fluphenazine hydrochloride 2-60 2 33 Fluphenazine decanoate NA NA 12.5–50 every 1–4 weeks Thioxanthienes Thiothixene hydrochloride 5-30 5 2-4 34
Drug Name Dosage range Approximate oral dose Equivalents Parenteral dosage T1/2 Ziprasidone 80-160 40 10 7 Risperidone 4-8 1 25-50 mg/week 24 Quetiapine 150-600 100 NA 6 Clozapine 100-900 50 NA 12 Sertindole 12-24 4 NA Olanzepine 10-20 4 33 Aripiprazole 10-30 mg NA 75 Asenapine 10-20 mg Bifeprunox 20 mg Zotepine 75-300 NA Amisulpiride 50-1200
Speed and onset of antipsychotic drug action How long one should wait before initiating a change in dose or medication? The standard teaching being that the ‘onset’ of antipsychotic action may take anywhere from 2 to 4 weeks. There is a distinct onset of an antipsychotic effect within the first week, nearly 22% improvement in the first 2 weeks and only 9% improvement in weeks 3 or 4. There is a specific effect on psychotic symptoms within the first week, not just a non-specific effect on agitation and hostility. Newer studies show that if a patient does not demonstrate a certain amount of clinical response (currently thought to be about 20% symptom score reduction in the first 2 weeks), the patient has a rather low chance of response on that drug and dose in the future.
Clinical observation during the first 2 weeks of antipsychotic treatment is vital. Recognised rating scales should be used to monitor change. Where there is no response at 2–3 weeks, treatment should be changed (switch drug or increase dose). Where there is some response, staying, switching and augmenting appear to be equally, albeit modestly effective.
Treatment options for a patient not responding to antipsychotic therapy If dose has been optimised , consider watchful waiting. Consider increasing antipsychotic dose according to tolerability and plasma levels. If this fails, consider switching to olanzapine or risperidone (if not already used). If this fails, use clozapine (supporting evidence very strong). If clozapine fails, use time-limited augmentation strategies (supporting evidence variable).
Antipsychotic drugs: long-acting injections Antipsychotic long-acting injections (LAIs), also called depot antipsychotics. Advice on prescribing long-acting injections of antipsychotic drugs- For FGAs, give a test dose. Begin with the lowest therapeutic dose. Administer at the longest possible licensed interval. Adjust doses only after an adequate period of assessment. Depot preparations are not recommended for those who are antipsychotic-naive.
Reducing the dose of maintenance antipsychotic treatment Consider- symptom free period, severity of the side-effects, previous pattern of illness, Has dosage reduction been attempted before? If so, what was the outcome? current social circumstances, are stressful life events anticipated? Is the patient able to monitor his/her own symptoms? If so, will he/she seek help?
Reducing dose of depots- oral antipsychotic medication should be discontinued first. The interval between injections should be increased to up to 4 weeks before decreasing the dose given each time. Note: not with risperidone . The dose should be reduced by no more than a third at any one time. Decrements should, if possible, be made no more frequently than every 3 months, preferably every 6 months. If the patient becomes symptomatic, this should be seen not as a failure but rather as an important step in determining the minimum effective dose that the patient requires.
Combined antipsychotic drugs There is very little evidence supporting the efficacy of combined antipsychotics. Substantial evidence supports the potential for harm, therefore the use of combined antipsychotics should generally be avoided. As a minimum requirement, all patients who are prescribed combined antipsychotics should have their side-effects systematically assessed (including electrocardiogram monitoring) and any beneficial effect on symptoms carefully documented.
High-dose antipsychotic drugs: prescribing and monitoring ‘ High dose ’ can result from the prescription of either : a single antipsychotic in a dose that is above the recommended maximum, or two or more antipsychotics that,when expressed as a percentage of their respective maximum recommended doses and added together, result in a cumulative dose of >100%.
High-dose antipsychotic drugs: prescribing and monitoring
Omega-3 fatty acids (fish oils) in schizophrenia A seminal study of 700 mg EPA + 480 mg DHA in adolescents and young adults at high risk of psychosis showed that such treatment greatly reduced the emergence of psychotic symptoms compared with placebo. Fish oils are tentatively recommended for the treatment of residual symptoms of schizophrenia but particularly in patients responding poorly to clozapine . Careful assessment of response is important and fish oils may be withdrawn if no effect is observed after 3 months’ treatment, unless required for their beneficial metabolic effects. Doses- Omacor (460 mg EPA) 5 capsules daily/ Maxepa (170 mg EPA) 10 capsules daily
Side-effects of Antipsychotics
EPS - acute dystonias , akathisia , parkinsonism (rigidity and tremor) Constipation, dry mouth and blurred vision. Tachycardia, hypotension, QTc prolongation. Lethargy, hyperprolactinaemia , sexual and menstrual problems. Metabolic - weight gain, Diabetes, Dyslipidemia S/e of clozapine .
Extrapyramidal syndrome treatment Acute dystonia (an abrupt, painful contraction of one or more skeletal muscle groups) is an idiosyncratic reaction to the dopamine blocking effects of antipsychotic medications. Prompt administration of benztropine 1-2mg po /IM or diphenhydramine 50-100mg po /IM can reverse dystonia . IM administration may result in more rapid reversal of dystonia than oral administration. Response to IV administration will be seen within 5 min. Response to IM administration takes around 20 min. Tardive dystonia may respond to ECT. Where symptoms do not respond to simpler measures including switching to an antipsychotic with a low propensity for EPS, botulinum toxin may be effective.
Treatment of antipsychotic-induced akathisia
Treatment of antipsychotic-induced akathisia Note that severe akathisia may be linked to violent or suicidal behaviour . Evaluate efficacy of each treatment option over at least 1 month. Some effect may be seen after a few days but it may take much longer to become apparent in those with chronic akathisia .( tardive akathisia ) Withdraw previously ineffective akathisia treatments before starting the next option in the algorithm. Combinations of treatment may be used in refractory cases if carefully monitored. Other possible treatments for acute akathisia include vitamin B6, diphenhydramine , trazodone and zolmitriptan .
Treatment of tardive dyskinesia Treatment of established TD is often unsuccessful, so prevention and early detection are essential. Most authorities recommend the withdrawal of any anticholinergic drugs and a reduction in the dose of antipsychotic as initial steps in thosewith early signs of TD. (dose reduction may initially worsen TD). It has now become common practice to withdraw the antipsychotic prescribed when TD was first observed and to substitute another drug. The use of clozapine is probably best supported in this regard, but quetiapine , another weak striatal dopamine antagonist, is also effective. Olanzapine is also an option. Switching or withdrawing antipsychotics is not always effective and so additional agents are often used.
Treatment of tardive dyskinesia
Neuroleptic malignant syndrome Main clinical features include (1) hyperthermia; (2) severe muscular rigidity, (3) autonomic instability including hyperthermia, tachycardia, increased blood pressure, tachypnea , and diaphoresis, and (4) changing levels of consciousness. These symptoms are often associated with elevations in creatine phosphokinase (CPK) and aldolase . Less common are elevations in liver transaminases , leukocytosis , myoglobinemia , and myoglobinuria . Mortality ranging from 20 to 30 percent and may be higher when depot forms are used.
Treatment- Neuroleptics should be discontinued and supportive and symptomatic treatment should begin. This includes correcting fluid and electrolyte imbalances, treating fevers, and managing cardiovascular symptoms such as hyper- or hypotension. Consider benzodiazepines if not already prescribed – IM lorazepam has been use. Bromocriptine can then be added at doses of 20 to 30 mg daily in four divided doses. Dantrolene ( Dantrium ) may be effective for treating severe NMS. Amantadine may be helpful if the other agents are not sufficient.
Hyperprolactinaemia Hyperprolactinaemia is often superficially asymptomatic. Nonetheless, persistent elevation of plasma prolactin is associated with a number of adverse consequences. These include sexual dysfunction, reductions in bone mineral density, menstrual disturbances, breast growth and galactorrhoea , suppression of the hypothalamic-pituitary- gonadal axis and a possible increase in the risk of breast cancer. All patients should have their prolactin concentration measured before starting an antipsychotic.
Prolactin -elevating drugs ( amisulpride , sulpiride , risperidone , FGAs) should, if possible, be avoided in the following Patients under 25 years of age (i.e. before peak bone mass) Patients with osteoporosis, Patients with a history of hormone-dependent breast cancer.
Symptoms (reduced libido, infertility) are usually seen with prolactin levels above 31–50 ng /ml (∼660–1060 mIU /L). When levels exceed 100 ng /ml (∼2120 mIU /L) there is usually galactorrhoea and amenorrhoea .
Treatment of hyperprolactinaemia -For most patients with symptomatic hyperprolactinaemia , a switch to a non- prolactin elevating is the first choice. An alternative is to add aripiprazole to existing treatment. Established antipsychotics not usually associated with hyperprolactinaemia - Aripiprazole Clozapine Olanzapine Quetiapine Ziprasidone
Treatment resistant schizophrenia Failure to respond to at least two antipsychotics(adequate dose and duration) The issue of treatment resistance is of particular importance for practicing psychiatrists, because a)10% to 30% of patients have little or no response to antipsychotic medications, and b) Up to an additional 30% of patients have only partial responses to treatment. The concept of non response to treatment is multidimensional, as no response may be present in positive, negative, cognitive, excitement, or depressive symptom domains
Management of Resistant schizophrenia Clozapine Psychotherapy Electroconvulsive th erapy Repetitive transcranial magnetic stimulation ( rTMS ).
Clozapine has two FDA indications The treatment-resistant schizophrenia Risk reduction of recurrent suicidal behavior
Psychosocial treatments
Individual Psychotherapy Individual psychotherapy involves regularly scheduled talks between the patient and a mental health professional The sessions may focus on current or past problems, experiences, thoughts, feelings or relationships. By sharing experiences with a trained empathic person (talking about their world with someone outside it) individuals with schizophrenia may gradually come to understand more about themselves and their problems. Recent studies indicate that supportive, reality-oriented, individual psychotherapy, can be beneficial for outpatients with schizophrenia.
Family education It is important that family members learn all they can about schizophrenia and understand the difficulties and problems associated with the illness. It is also helpful for family members to learn ways to minimize the patient’s chance of relapse — for example, by using different treatment adherence strategies — and to be aware of the various kinds of outpatient and family services available in the period after hospitalization. Family “ psychoeducation ,” which includes teaching various coping strategies and problem-solving skills, may help families deal more effectively with their ill relative and may contribute to an improved outcome for the patient.
Self help groups Although not led by a professional therapist, these groups may be therapeutic because members provide continuing mutual support as well as comfort in knowing that they are not alone in the problems they face. Self-help groups may also serve other important functions. Families working together can more effectively serve as advocates for needed research and hospital and community treatment programs. Patients acting as a group rather than individually may be better able to dispel stigma and draw public attention to such abuses as discrimination against the mentally ill. Family and peer support and advocacy groups are very active and provide useful information and assistance for patients and families of patients with schizophrenia.
Social Skills Training Social skills are those "…specific response capabilities necessary for effective social performance“ . Social skills training uses learning theory principles to improve social functioning by working with patients to remediate problems in activities of daily living, employment, leisure, and relationships. It is hoped that the improved skills (primary outcome) will generalize to better community functioning and have a downstream effect on relapse and psychopathology. There are three forms of social skills training: the basic model, the social problem-solving model, and the cognitive remediation model.
Vocational rehabilitation Competitive employment (holding a regular community job as opposed to being employed in a program overseen by a rehabilitation agency) has been estimated at less than 20% or probably lower for patients with schizophrenia . In an effort to keep patients as functional and autonomous as possible, various programs have been implemented to help patients find jobs and maintain them. Supported employment programs, the most recent approach to enhancing outcomes , aims to improve opportunities for competitive employment. However, several common components across models may be identified, including a goal of permanent competitive employment, minimal screening for employability, avoidance of preoccupational training, time-unlimited support, and consideration of client preferences
Cognitive Behavior Therapy Over the past decade, there has been a growing interest in applying cognitive behavior therapy techniques to persons with schizophrenia, particularly those who continue to experience psychotic symptoms despite optimal pharmacological treatment. The principal aims of cognitive behavior therapy for medication-resistant psychosis are to reduce the intensity of delusions and hallucinations (and the related distress) and promote active participation of the individual in reducing the risk of relapse and levels of social disability. Interventions focus on rationally exploring the subjective nature of the psychotic symptoms, challenging the evidence for these, and subjecting such beliefs and experiences to reality testing.
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