- 1 Bioethical Issues In Psychopharmacological Research
- 2 Introduction To Atypical Antipsychotics
- 3 Nonantipsychotic Effects Of Atypical Antipsychotics
- 4 Are Atypical Antipsychotics Better Than Conventional Antipsychotics?
- 5 Indications For Antipsychotic Treatment
- 6 Use Of Atypical Antipsychotics In Aggressive Behavior
- 7 Choosing Antipsychotic Medications
- 8 Is There An Appropriate Time To Initiate Antipsychotic Medications?
- 9 Does The Timing Of Initiation Of Treatment Of Psychosis Influence Prognosis?
- 10 Clinical Applications Of Atypical Neuroleptics
- 11 Strength Of Atypical Antipsychotic Research Data
- 12 Issues Regarding Treatment With Antipsychotic Medications In Children And Adolescents
- 13 Baseline Studies For Antipsychotics Workup
- 14 Recommendations For The Use And Selection Of Antipsychotics
- 15 Clinical Use of Antipsychotic Medications: Medication Monitoring
- 16 Drug Choice And Dosage
- 17 Phases Of Treatment
- 18 Clinical Use of Antipsychotic Medications: Compliance And Therapeutic Adherence
- 19 Side Effects Monitoring
- 20 Discontinuation Of Antipsychotics And Switching Of Antipsychotics
- 21 Related Posts
Considerations in the Clinical Use of Antipsychotic Medications
The following assertions summarize the issues discussed in this post:
- • Antipsychotic medications are key components in the comprehensive treatment program of severely mood dysregulated children and adolescents with psychotic symptoms, and for children and adolescents with psychotic disorders.
- • The second generation antipsychotics seem to offer advantages over classical antipsychotics, but they do have their own disadvantages.
- • The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) report raises questions regarding the role of the first generation antipsychotics and of perphenazine in particular, in the treatment of adult schizophrenia. Perphenazine performed as well as most of the atypical studied (risperidone, quetiapine, ziprasidone, except for olanzapine which demonstrated a gradient of therapeutic superiority over all the medications tried, including perphenazine); olanzapine was, however, the most adiposogenic and prodyslipidemic antipsychotic.
- • For some second generation antipsychotics, the purported advantages are counterbalanced by deleterious health risks: metabolic, cardiovascular, and others. Cost of medication is an increasing concern.
- • The second generation antipsychotics have important tymoleptic functions: they demonstrate antimanic and antidepressant effects.
- • Most of the knowledge base in the conceptualization and treatment of psychotic disorders in children and adolescents is derived from adults. It is encouraging that research of second generation antipsychotic medications in pediatric populations is on the rise.
- • By and large, there are no evidence-based data to support the broad and extensive use of antipsychotics in children and adolescents.
- • Atypical antipsychotics may pose serious health risks for children and adolescents; these medications can aggravate certain medical conditions or be the cause of new medical complications.
Bioethical Issues In Psychopharmacological Research
Fegert (2003) asserts that the present cautionary rules against children’s participation in research (Nuremberg Code, the Helsinki Convention, European Bioethical Convention) is actually unethical because the protective regulations may contribute not to the avoidance of risk but to the increase of risk for children and adolescents. In usual clinical practice the risks and benefits of treatment are borne individually by patients and doctors, and are usually determined scientifically on the basis of clinical trials. Without the appropriate scientific data being available these risks and benefits cannot be determined appropriately. In the United States, investigative commissions were formed following reports of previous medical abuse. In the Belmont Report, the National Commission for the Protection of Human Subjects (1978) formulated four fundamental principles for medical ethics requirements: freedom from harm, healing (care), justice, and respect for the patient’s autonomy. Fegert states that the application of those bioethical principles to the psych opharmacological treatment of psychosis in children and adolescents mean, among other things:
- 1. Need for effective therapies, free from side effects, as much as possible, in both acute and long-term treatments. This meets the requirement of freedom from harm.
- 2. Attainable therapeutic goals. This meets the requirement for healing and care.
- 3. Children, as a group, should receive at least the same degree of protection and same kind of safety and quality of treatment as adults. This meets the requirement for justice.
- 4. Child and adolescent psychiatrists must facilitate children and adolescents’ greatest participation possible in treatment decisions, even in patients suffering from a severe psychosis. This meets the requirement for autonomy.
In order to increase children and adolescents’ benefits from research participation, Fegert advises that:
- 1. The treatment of children and adolescents with schizophrenic psychoses (and other psychoses) must proceed under the same scientific standards of safety as in adult medicine.
- 2. Due to legal stipulations, at present, there exists a persistent uncertainty that is frequently passed on as a legally binding question to the person in custody, and to the patient being treated, because the pharmaceutical firms will refuse liability if the substance is used in an off-label context.
- 3. Precisely in such situations, sufficient consultation with parents is, from both an ethical and medical-legal perspective, the main precondition for responsible action,
Are children able to consent to treatment? Some researchers consider that the construct of informed consent becomes a construct that goes against the best interest of children. During treatment and consultations, parents behave as addressees on behalf of the children although the children are expected to cooperate in the treatment. A distinction is being made between assent and consent, understanding by assent the child or adolescent s willingness to undergo treatment which, though it does not have the status of legal consent, is still an important prerequisite for clinical research.
A hopeful and encouraging development in future pharmaceutical research is the expectation that the upcoming new drugs will be required to be tested on sensitive populations: women of childbearing age, children and adolescents, and the elderly.
Clinicians underestimate children’s (adolescents, and even late latency children’s) capacity for understanding the complexities of risk-benefit assessment and to make decisions on their own behalf. Clinicians take a paternalistic or even a patronizing attitude toward children and adolescents because they suffer from a serious mental disorder, but even under these clinical circumstances, children and adolescents can assent to treatment, and participate in major decisions regarding treatment choices.
Nonantipsychotic Effects Of Atypical Antipsychotics
The new group of neuroleptic medications has mood modulating functions and antiaggressive activities besides their represented antipsychotic effects; because of that, an appropriate nomenclature for these medications would be welcome. Because of the multiple receptor affinities (which explain their broad therapeutic effects), atypicals have received the colorful label of “promiscuous drugs.” In this regard, Swartz (2003) argues that atypicals are nonspecific antischizophrenic drugs: they have demonstrated effectiveness for most of the established psychiatric Axis I and II diagnoses, regardless of the presence of psychosis in those conditions. Atypical antipsychotic medications also have demonstrated some efficacy in the treatment of cognitive deficits of schizophrenia.
Some atypicals may decrease the life span due to long-term metabolic, endocrinological, or cardiovascular side effects, including the risk of sudden death. In addition, “atypical antipsychotics as a group were found to have significantly higher frequencies of EEG abnormalities than typical neuroleptics at each step of the four-level EEG abnormality rating scores”. Each atypical antipsychotic has its own side effect profile risk; clinicians need to familiarize themselves with the health risks of each atypical antipsychotic.
Choosing Antipsychotic Medications
A number of issues need to be taken into account in the selection of antipsychotic medications (see TABLE Issues that Need to be Considered in the Selection of Antipsychotic Medications).
Despite the lack of controlled studies, the American Academy of Child and Adolescent Psychiatry practice parameters and recent pediatric psycho-pharmacological review articles favor atypical antipsychotics agents as the “Standard of Care” for children and adolescents with psychotic conditions. Prevailing clinical thinking and psychiatric practice recommend the second generation agents over the first generation ones. However, greater experience with atypical antipsychotics (strengths and limitations) make the Patient Outcomes Research Team (PORT) recommendations from 1998 still valid: “We do not recommend preferential use of second generation agents over first generation ones but rather focus on the wider options now available to clinicians and patients in selecting the best treatment for the individual”.
TABLE Issues that Need to be Considered in the Selection of Antipsychotic Medications
|• Nature of the therapeutic alliance|
|• Nature of the psychiatric condition|
|• Specific target signs and symptoms|
|• History of family medication response|
|• Past history of medication response (therapeutic and adverse events)|
|• Patient preference|
|• History of treatment adherence|
|• History of medication effectiveness|
|• Presence of medical and psychiatric comorbidity|
|• Nature of concomitant medications|
|• Availability of appropriate formulations (vehicles or medication presentation), e.g., fast-dissolving oral, short- and long-acting intramuscular|
|• Medication costs|
|• Access to and availability of medications|
|• Risk of obesity, diabetes and dyslipedimias.|
Does The Timing Of Initiation Of Treatment Of Psychosis Influence Prognosis?
Some investigators have expressed concerns that if treatment of schizophrenia is not started early and promptly, the therapeutic response is decreased and the prognosis is compromised. Do not find support for these concerns. In their view, “On the basis of our findings as well as [those of] other investigators… the pattern of mostly small correlation coefficient and the paucity of significant differences between patients with long and short duration of untreated initial psychosis do not support the frequently expressed belief that long periods of untreated psychosis have a pronounced impact on neurocognitive functioning or on brain morphology in schizophrenia”. These authors argue that structural brain abnormalities and cognitive deficits are evident by the time patients first come to treatment, that the neurodevelopmental theory of schizophrenia posits that abnormal or genetic factors interfere with early brain development (neurulation, cellular proliferation, migration, differentiation, and synaptogenesis), and that later brain development processes (e.g., apoptosis and synaptic pruning) or neurodevelopmental events (e.g., stress, illicit drugs, head trauma) interact with the already aberrant neuropathology to produce the symptoms and signs of schizophrenia. Thus, the structural brain abnormalities and cognitive deficits found in schizophrenic patients maybe primarily neurodevelopmental in origin. Several studies have shown that schizophrenic patients with poor outcome exhibit greater ventricular enlargement over time, suggesting that additional pathogenic processes may contribute to further deteriorative progression in these deficits. If such pathogenic processes are also present around the onset of clinical symptoms, it appears that untreated psychosis is not a contributing factor. The authors substantiated their proposition on a later neuroimaging study. The authors concluded, again, that there were no significant associations between hippocampal volumes and duration of untreated initial psychosis.
A Scandinavian study conducted by Rund et al. (2004) corroborated Ho, Alicata, et al.’s (2003) findings (cited above). This was a large study group: the number of patients participating in the study was larger than in any prior studies of its kind. Also, the neuropsychological test batteries included tests of a wider range of cognitive functions compared to former studies. The Scandinavian authors found no association between duration of untreated psychosis and any of the cognitive measures. Strong associations were demonstrated between poorer premorbid school functioning and neurocognitive deficits, especially in verbal learning and working memory. No relationship was found between neurocognitive functions and clinical measures except for an inverse correlation of positive and negative syndrome scale and working memory, and a positive correlation between positive symptom and motor control. The authors did not find any correlation between medication types (first generation antipsychotics vs. second generation antipsychotics) or dose and neuropsychological results, either.
Clinical Applications Of Atypical Neuroleptics
In general, atypical antipsychotics have broad antischizophrenic effects (for both positive and negative symptoms) and positive mood modulating effects. Some atypicals appear to have positive effects on cognitive functioning. There is a growing application of atypical medications to a broad variety of psychotic and mood disorders (mostly bipolar disorders), aggressive behaviors, movement disorders, and in many other psychiatric conditions. Gracious and Findling (2001) suggest the following indications (see TABLE Common Uses of Atypical Antipsychotics in Children and Adolescents).
TABLE Common Uses of Atypical Antipsychotics in Children and Adolescents
|Brief psychotic disorder|
|Psychotic disorder NOS|
|• Mood disorders|
|Treatment resistant bipolar disorder|
|Bipolar disorder with psychotic features|
|Major depression with psychotic features|
|• Movement disorders|
|Tic disorders or Tourette’s syndrome|
|Stereotypic movement disorder|
|• Autism and pervasive developmental disorders|
|• Intermittent explosive disorder|
|Common uses in pediatric medicine”|
|• Sedation; paradoxical response to benzodiazepines|
|• Drug-induced (e. g., steroids) psychosis|
|• Delirium (e. g., meningitis or ketoacidosis)|
|• Organic personality disorder|
|• Agitation (hospitalization or immobilization)|
|• Self-injurious behavior (e. g., biting)|
|• Anorexia nervosa|
|Potential uses in child psychiatry:|
|• Disruptive behavior disorders|
|Severe or treatment resistant ADHD|
|• Schizoid or schizotypal personality traits|
|• Borderline personality traits|
|• Severe stuttering|
There is no research evidence indicating that either first or second generation antipsychotics were effective for primary negative symptoms of schizophrenia, although they are useful for negative symptoms secondary to positive psychotic symptoms. Lamotrigene has shown positive results on negative symptoms on both bipolar disorders and schizophrenia. Because of the broad-spectrum therapeutic effects, the atypicals act as a “pharmacological shotgun” treatment on a variety of aspects of the disease (schizophrenia) in all patients. Many clinicians are using the broad unspecific therapeutic effects to deal with a multitude of clinical issues in their practice. A more rational and more sophisticated and perhaps more effective approach to schizophrenia (and other psychotic conditions) may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e., positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.
Strength Of Atypical Antipsychotic Research Data
Based on the strength of the research evidence, Jobson and Potter (1995) categorized available data at the following levels:
Level A: Data is supported by two or more randomized control trails. There is good research-based evidence supporting a clinical recommendation.
Level B: Data is supported by at least one randomized trial. There is fair research-based evidence supporting a clinical recommendation.
Level C: Data is supported by opinion, case reports, and studies that do not meet randomized, controlled-trial criteria. Data is primarily based on group opinion, with minimal research-based evidence to support a clinical recommendation. Lack of evidence does not mean lack of efficacy
Issues Regarding Treatment With Antipsychotic Medications In Children And Adolescents
No psychopharmacological treatment should be initiated without a comprehensive assessment including, developmental and family history, previous response to medications (including family members’ response), review of systems, and a physical and neurological examination. Blood tests, EKG, and baseline laboratory tests are indicated; other studies may be necessary dependent on the patients individual and medical circumstances.
The physician should anticipate adverse event effects and will request pertinent tests to monitor the potential side effects of the prescribed antipsychotic. Physicians will remind families and patients that all antipsychotic and mood stabilizing medications with FDA indication(s) for adults, do not have FDA indication for use in childhood and that children, as a group, have more frequent and more severe adverse event reactions than adults.
There is a growing concern with the expanding practice of polypharmacy in childhood. This is one of the most critical issues that must be studied. Child psychiatrists seem to be progressively complaisant about the practice of polypharmacy. It seems that the psychiatry field is becoming less concerned and probably less attentive to polypharmacy increased risks.
Baseline Studies For Antipsychotics Workup
Current standards of practice demand a comprehensive physical and neurological examination plus a variety of laboratory examinations prior to the initiation of antipsychotic medication. Child and adolescent psychiatrists need to pay attention to a number of issues prior to, and during the prescription of antipsychotics as suggested, with modifications by Bryden, Coletti, Dicker, et al. (2001; for baseline assessments before initiation of treatment of antipsychotic
medications see TABLE Baseline Assessments for Antipsychotic Treatment).
TABLE Baseline Assessments for Antipsychotic Treatment
|Physical examination (pulse, blood pressure)|
|Weight and height (BMI, measurements of waist and hip circumference)|
|AIMS, extrapyramidal side effects, Barnes, Simpson-Angus assessment scales|
|CBC, hepatic, renal and thyroid function|
|Insulin level, hemoglobin Ale|
|Urine drug screen|
|Glucose and lipid profile|
|Lactate, pyruvate, and ketone levels to rule out mitochondrial disorders|
|EKG: QTc Interval.|
|CSF studies to rule out occult CNS infections.|
Drug Choice And Dosage
Except for the CATIE I study there is no definitive study that demonstrates superiority of one atypical antipsychotic over another one. “Despite the publication of several treatment guidelines, there is significant variation in pharmacological treatment practice that cannot be explained away by ‘patient heterogeneity’ Efforts to promote evidence-based ‘best possible’ pharmacotherapy of schizophrenia have hitherto been unsuccessful”. Obviously these concerns are even more important in regard to the use of antipsychotics in children. The CATIE study showed that olanzapine has a gradient of therapeutic effectiveness superiority over the other comparator antipsychotics (perphenazine, quetiapine, ziprasidone, risperidone). The CATIE II results substantiated the therapeutic superiority of clozapine and corroborated the gradient of superiority of olanzapine over risperidone and quetiapine in the treatment of chronic adult schizophrenics.
Treatment of bipolar disorders in childhood is empirical; there are no established norms for the treatment of pediatric bipolar disorder. Although second generation antipsychotics are demonstrating antimanic efficacy in adults, there are no rigorous controlled studies demonstrating similar effects in childhood. Furthermore, most of the evidence-based studies in adults are short-term. The reader will be reminded that the current accepted view is that bipolar pediatric disorders are chronic conditions.
Bryden, Coletti, Kutcher, et al. (2001) recommend a very conservative optimal dose for atypicals, 300 mg chlorpromazine equivalents/day and, (1) attention to clinical status, physical heath, and prior medication response; (2) monitoring for clinical response; (3) change of the antipsychotic if no response in six weeks or earlier, or if side effects become intolerable. Bryden, Coletti, et al.’s conservative dose recommendations are applicable to children and adolescents with moderate psychopathology. For children with severe psychosis, clinicians use more often than not, doses that are akin to levels used in adult patients, that is, 600 to 800 mg of chlorpromazine equivalence dose/day, or even higher. There are multiple issues related to the use of antipsychotic medications at doses above the recommended levels (see TABLE Caveats in the Prescription of High Dose Antipsychotics).
TABLE Caveats in the Prescription of High Dose Antipsychotics
|Patient may not be responding for lack of adherence.|
|1. Attend to psychosocial stressors and to adherence to psychosocial interventions.|
|2. Change on medications may not be needed.|
|3. Attend to GADE (Genetic variation, Age, Disease, Environmental factors).|
|4. There is no evidence-based support for the use of high dose antipsychotics. Unpublished cases in which high dose therapy was ineffective may outnumber published positive reports.|
|5. Current dose concentration may be too high and the resulting adverse effects may resemble worsening of the disease being treated.|
|6. Rapid medication clearance should be considered.|
|7. Higher doses may not help. Higher doses may decrease effectiveness.|
|8. Higher doses increase adverse events and costs, adding pressure for noncompliance.|
|9. Most of the reports on higher doses are anecdotical and uncontrolled.|
|10. Antipsychotics work in 6 to 8 weeks. Increases above the recommended doses are not advised during the initial 6 to 8 weeks.|
|11. Polypharmacy may cloud attributions of clinical response.|
|12. Oversedation does not equal improvement.|
|13. If higher doses are tried, increase monitoring and attend to added potential risks.|
Phases Of Treatment
In the use of antipsychotic medications, Tandom, as reported by Bowes (2002), identifies three distinct treatment phases, each with its own characteristics and treatment goals: acute, symptom resolution phase, and long-term maintenance phase. This scheme is also applicable for considerations of pediatric bipolar treatment. In the treatment of children and adolescents with severe psychotic disorders, we propose parallel treatment chronology goals to Tandom’s scheme:
Promoting a therapeutic alliance for the initiation of treatment. Oftentimes, families are in shock, and it is hard for them to accept that the child has a serious psychotic illness. Efforts are directed toward breaking the individual and family denials, and to promoting the child and family’s alliance for the initiation of multimodal treatments. Since antipsychotic medication is one of the pillars for improvement or resolution of the psychotic process, it is imperative to educate the family on the nature of the psychotic illness, and to discuss at length the antipsychotic target symptoms and the nature of medication side effects. Both child and family should be given ample opportunity for discussing benefits and potential medication risks. A parallel consideration will be given to the use of a mood stabilizer in childhood. Psychiatrists will propose target symptoms and will educate patients and families about potential side effects, including a full explanation of each medications “blackboxes” or serious warnings, when pertinent.
The psychiatrist monitors medication compliance and adherence to other psychosocial interventions. The clinician needs to methodically monitor adaptational stressors at school, at home, in the social milieu (parental discipline and consequences), and also becomes vigilant for signs of alcohol or drugs abuse.
This is the maintenance phase in which the psychiatrist continues monitoring for early evidence of psychotic or mood disorder relapse, and for medication and psychosocial interventions adherence. If the child maintains stability for an extended period, the psychiatrist will attempt to use lower therapeutic doses. The psychiatrist will also pay attention to the patient’s health and other aspects of the patient’s development, and will monitor his or her response to the comprehensive rehabilitation program. The psychiatrist monitors and promotes optimal child functioning at the school, within the family, and in the social milieu. All along, the psychiatrist will keep in mind that medication side effects are a major hindrance to treatment compliance; thus, detailed exploration of medication side effects should be done systematically in each therapeutic contact. Long-term side effects such as tardive dyskinesia, weight gain, diabetes, dyslipedimias, cardiovascular, and others require attentive monitoring. Females are particularly sensitive to side effects that may affect their perceived attractiveness and gender role functioning: weight gain, hair loss, acne, polycystic ovarian disease, and others.
Clinicians need to be attentive to any source of developmental interference and, if found, it should be addressed appropriately and without delay. Developmental interference refers to any detrimental influence from the psychosocial milieu that interferes with normal child and adolescent development.
Side Effects Monitoring
Broad questions regarding the presence of side effects are not effective in introducing and exploring the topic of side effects and the problems of compliance. A good start is to ask the patient what problems have arisen with the medications, and then, to explore systematically the presence of GI, sedative (Is the child sleeping in class?), cognitive/learning (Is the child keeping up with her grades?), memory, concentration (Are medications interfering with attention and learning?), or language interference (Is the child experiencing difficulties in word finding? Is the child having problems making or completing sentences?). Are there balance or coordination problems? How is the appetite? (Is the patient gaining weight? Is the child eating more than before?). Any sleep problems? Does the child complain of difficulties falling sleep or of waking up in the middle of the night? Any neuromuscular side effects (tremor, extrapyramidal side effects?), any sexual side effects? Male adolescents may complain about erectile or ejaculatory difficulties. Sexual side effects need to be inquired about in sexually active adolescents. Only when the psychiatrist takes into account the patient’s point of view, may issues related to noncompliance, and other treatment adherence obstacles be revealed, understood, and worked through.
Parents are very apprehensive regarding side effects that produce sedation (more so if the child sleeps in class), constriction of affect (parents miss the sense of liveliness of the child), and overweight (because of teasing, or because of personal complaints from the child). Any of these side effects render compliance very difficult.
Adherence is likely when the physician listens to the patient’s concerns regarding medication side effects. Taking the complaints related to medication side effects seriously is a powerful intervention in itself. When patients feel understood they are better able to trust their psychiatrists and to follow the treatment recommendations and be open about nonadherence and the emergence of side effects. Actually, the patients should be encouraged to report side effects; this increases the therapeutic alliance.
The key to medication education is to translate our notion of symptoms into something the patient considers being a problem, which can be helped with the medication. When emphasizing adherence to avoid relapse and re-hospitalization it is probably a better strategy for the physician to inquire about life and future goals. In this manner, the clinician may hear about the patient’s desire to go back to school, to work, or to have a romantic involvement. The psychiatrist may articulate to the child and the family how adherence to treatment recommendations may help the child to achieve those goals.
The literature shows a strong correlation between therapeutic alliance, medication adherence, and outcomes in chronic psychosis, and probably, in chronic psychiatric illness. Although medications are important, medications alone are not enough. Patients who have a good relationship with their doctors are more likely to stay on medications, less likely to relapse, and generally will do better in other aspects of their lives. Doctors need to strive to create a therapeutic alliance and to strengthen the alliance in every contact with the patient. A good alliance helps to foster supportive relationships outside of the family and to strengthen the therapeutic relationship with the family and other supportive persons or systems, in the child’s life.
1. In this writer’s opinion, the lessons from the CATIE trial are:
Antipsychotics in general, and second generation antipsychotics (second generation antipsychotics) in particular, leave much to be desired in terms of effectiveness, tolerability, and staying power.
First generation antipsychotics (first generation antipsychotics) are not dead; it is likely that as a result of the performance of perphenazine, this medication and probably other first generation antipsychotics may be reconsidered as viable alternatives for the treatment of chronic psychosis and related symptoms.
Olanzapine showed some gradient of superiority in therapeutic effectiveness and staying power over the comparators: perphenazine, quetiapine, risperidone, and ziprasidone. However, (i) this medication was prescribed at higher doses than recommended in the 2006-PDR, and (ii) olanzapine’ adiposogenic and prodyslipidemic side effects were the highest among the antipsychotics tried (risperidone, quetiapine, ziprasidone and perphenazine).
The cardiotoxicity of ziprasidone has been overstated. Another way of saying this is to assert that ziprasidone cardiotoxicity is comparable in risk to one of olanzapine, perphenazine, risperidone, or quetiapine.
Ziprasidone was the only antipsychotic among the agents tried that had beneficial effects in weight and other metabolic parameters.
2. The CAFE trial, Comparison of Atypicals in First-Episode Psychosis: A Randomized, 52-week Comparison of olanzapine, quetiapine, and risperidone, conducted by Lieberman, McEvoy, et al. (2005), reflected parallel results to CATIE’s: 75.9% of patients were drug naive, and 57.8% received the diagnosis of schizophrenia. Mean daily modal doses were: olanzapine (N = 133), 11.7 mg; quetiapine (N = 134), 506 mg; risperidone (N = 133), 2.4 mg. At 52 weeks, the treatment discontinuation rates were, 68, 70.9, and 71.4%, respectively. There were no significant differences between treatments, except that fewer quetiapine patients received fewer concomitant medications for Parkinsonism or akathisia compared to olanzapine (3.7% vs. 11.3%). At week 52, 80% of olanzapine treated patients had gained more than 7% of baseline weight, compared to 57.6% (risperidone), and 50% in quetiapine-treated patients (P = 0.01). In the CATIE trial, the mean modal doses and rates for all cause discontinuation were, for olanzapine: 20.1 mg and 64%; for perphenazine: 20.8 mg and 75%; for quetiapine: 543.4 mg and 82%; for risperidone: 3.9 mg and 74%; and for ziprasidone: 112.8 mg and 79%, respectively.
3. Interesting research findings show that the long-term effect of different atypicals on rats’ basal ganglia is different for different drugs: There is an increase in volume in animals that received haloperidol or clozapine compared to control animals; the volume is significantly decreased in animals receiving olanzapine compared with controls; and no significant difference was seen in the risperidone-treated animals compared with controls. These drugs “are very different from each other, not only in what receptors they interact within the brain, but also in differences between low and high doses of the same drug affecting different receptor targets”.
4. Kapur, Arenovich, et al. (2005) demonstrated that onset of actions by antipsychotics (olanzapine and haloperidol) may start by the first day of treatment initiation. Their study supports previous reports of significant antipsychotic effects by the third day of treatment, and even a meta-analysis indicating that rate of improvement during the first week was superior to any other ensuing week. The authors proposed an “early-onset hypothesis.” This proposition is in line with a well-recognized, substantial blockade of the dopamine system by antipsychotic medications within the first few hours of treatment.
5. The atypical clinical effects are broad and powerful. Atypicals are prescribed for major depression without psychotic features, dysthymia, mania without psychotic features, bipolar II disorder, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, intermittent explosive disorder, insomnia, delirium, Tourette’s disorder, anorexia nervosa, personality changes due to neurological or developmental conditions, borderline personality disorder, catatonia, and probably others. Symptoms for which atypicals are prescribed include aggressive behavior, worrying, agitation, reactivity to environmental stimuli, social stress, insomnia, and mood disturbances. This parallels antipsychotic pediatric use.
6. Steiner, Saxena, and Chang (2005) consider primary and secondary disorders of aggression. Primary disorders include: oppositional defiant disorder (ODD), conduct disorder (CD), intermittent explosive disorder (IED), paraphilias, kleptomania, antisocial personality disorder (APD), borderline personality disorder (BPD), and pyromania. To the secondary group belong: attention deficit hyperactivity disorder, pervasive developmental disorder (PDD), autism, mental retardation (MR), anxiety disorders (PTSD, dissociative disorder, separation anxiety disorder, social phobia), mood disorders, especially bipolar disorder, substance abuse and dependency (SUD), schizophrenia and other psychotic illnesses, and bulimia. The authors also subdivide the primary disorders into reactive, affective, defensive, impulsive (RADI or “hot”), and planned, instrumental, proactive (PIP or “cold”). Different neuronal architectures support these processes. For secondary disorders of aggression, treatment of the dysfunctional module (syndrome) reduces aggressive behavior.
7. At the SMHC, where this author practices child and adolescent inpatient, partial hospitalization, and residential treatments, ziprasidone injectable has been used about 400 times, in doses ranging from 5 to 20 mg; most of the medication has been used with adolescents, and to a less extent with preadolescents. Most adolescents received 20 mg IM for agitation or behavior dyscontrol; preadolescents usually received 10 mg IM for related reasons. So far, we have not had the first untoward reaction. Of interest, and a great advantage of this medication vehicle, patients calm down without falling sleep. Most of the children resume therapeutic programming in less than 60 to 90 minutes after the injection. Seldom has the dose been repeated, and no patient has received more than 40 mg IM/day It is important to indicate that 20 mg of ziprasidone IM is equivalent to approximately 120 mg or probably more of oral dose.
8. A number of scales have been developed for the study of prodromal schizophrenia:
- Comprehensive Assessment of At Risk Mental State (CAARMS)
- Melbourne Criteria for Ultra-High Mental State Based on CAARMS
- Scale of Prodromal Symptoms (SOPS)
- Structured Interview of Prodromal Symptoms (SIPS)
- Criteria of Prodromal Symptoms (COPS)
- Schizophrenia Prediction Instrument for Adults (SPI-A)
9. The high dose range of olanzapine in the CATIE trial (up to 30 mg/day, 50% higher than the approved upper range of 20 mg/day) is undoubtedly the Achilles heel of the argument that olanzapine demonstrated better effectiveness as measured by the “all-cause discontinuation” parameter…. So the debate boils down to which [antipsychotic medication] is better in the decades-long management of schizophrenia: discontinuation after 3 to 5 months for efficacy/tolerability reasons or discontinuation after 6 to 8 months due to metabolic tolerability/safety reasons.
10. Only 22% of the subjects (N = 11 of 50) went one year without an exacerbation or relapse following medication discontinuation. By two years, 96% (N = 48) of the subjects had experienced an exacerbation (N = 28) or relapse (N = 20). The mean time to exacerbation or relapse, for the 48 subjects whose psychotic symptoms returned within the time frame of the study, was 235 days, or just under 8 months. The median time to exacerbation or relapse was 245 days. The two subjects who did not experience exacerbation or relapse within the time frame of the study were followed clinically and ultimately developed psychotic symptoms after drug withdrawal: one at 28 months and the other at 93 months (i.e., 7 years, 9 months). Only three (13%) were hospitalized within three months of exacerbation. The rest were successfully managed in outpatient therapy. “[W]e still do not automatically recommend long-term maintenance treatment after the first episode for every patient.
Selections from the book: “Psychotic Symptoms in Children and Adolescents: Assessment, Differential Diagnosis, and Treatment”, 2007