This section deals specifically with the use of atypical antipsychotics currently in use in the United States. In less than a decade, atypical antipsychotics have become the dominant force in the treatment of adult and childhood psychosis. As a result of this rapid change, the typical antipsychotics have been progressively relegated to the sidelines of psychiatry practice (this is particularly true in the United States). The CATIE report (2005) may revive interest in first generation antipsychotics.
This writer foresees a revival of some first generation antipsychotics in the field of psychiatry that likely may extend into the field of child and adolescent psychiatry. Because perphenazine was tried in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, there is a summary description of first generation antipsychotics in appendix B, followed by general considerations in the use of first generation antipsychotics, in the same appendix.
Although conventional antipsychotics have a therapeutic effect on psychotic features as a whole, and on positive schizophrenic symptoms in particular, this action is often achieved at a cost of mood and cognitive impairments. In general, the improvements in positive symptoms are frequently accompanied by an increase in negative symptoms or some cognitive dulling. It is possible that these effects are the result of overdosing of first generation antipsychotics. In the CATIE study (2005) perphenazine demonstrates as good or better tolerability than the other atypicals (risperidone, ziprasidone, quetiapine, and olanzapine at an average 200 mg of chlorpromazine/day).
The first generation of antipsychotics has as a primary mechanism the dopamine blockade. The second generation of antipsychotics also blocks the dopamine receptors, and in addition, has critical modulating effects on other neurotransmitter receptor and modulatory sites, particularly at the serotonin (5-HT) receptors.
Working memory may be impaired by a deficiency of dopamine D2 and D3 receptors and the chronic use of antipsychotic drugs, which block D2 receptors. Since D2 receptor densities are higher in children and adolescents than in adults, these effects may help to explain why children and adolescents are especially sensitive to adverse events affecting the CNS [some degree of cognitive dulling]. Because the absolute number of occupied receptors can be higher in the pediatric population than in adults, the probability of developing extrapyramidal side effects maybe increased.
A number of theories to explain the “atypicality” of the new neuroleptic medications have been proposed, including a high affinity for 5-HT2 receptors, a high affinity for dopamine D4 receptors, and a fast dissociation from the dopamine D2 receptor. It appears that the fast dissociation theory has a greater heuristic value.
The therapeutic appeal of the atypical antipsychotics seems based on their better tolerability (the CATIE study raises questions in this regard), and in what is described as a broader spectrum of therapeutic action. Atypicals are represented to be effective on positive and negative symptoms, to have a favorable effect on mood, and to have a capacity for sparing or even improving cognitive functioning (these assertions have not been clearly demonstrated). All these effects are proposed to enhance treatment adherence (and this is not necessarily so, either).
Carpenter (2001) expressed reservations about the purported broad-spectrum therapeutic effects of these medications:
Antipsychotic drugs are effective for psychosis but are not broadly antischizophrenic in therapeutic action. The new generation of drugs is less likely to cause negative symptoms and cognitive impairments (compared to haloperidol in most studies), but efficacy for primary negative symptoms has not been documented, and controlled-study evidence for pro-cognitive efficacy (rather than reduced adverse effects) is modest. These aspects of schizophrenia mainly account for a reduced quality of life and other functional outcomes,
It is likely that the purported advantage in cognition and negative symptoms from second generation antipsychotics results from the high first generation antipsychotics doses used as comparators. In the CATIE trials, perphenazine, at relatively low dose, 200 mg chlorpromazine/day equivalence, was as effective as quetiapine (up to 600 mg/day), risperidone (up to 6 mg/day), and ziprasidone (up to 120 mg/day). Olanzapine demonstrated some therapeutic superiority but it was used up to 30 mg/day, beyond recommended PDR levels.
Kapur and Remington (2001) reached similar conclusions to Carpenter’s cited above:
In summary then, the word atypical should mean an antipsychotic with low extrapyramidal side effects and lack of sustained prolactin elevation. Effects on a number of other features of schizophrenia, such as negative symptoms, mood, cognition, and functional outcome, are all very desirable clinical therapeutic goals. However, they are neither consistently realized nor of a substantial magnitude with the current generation of antipsychotics.
In the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trials there was no significant difference among the antipsychotics tried (perphenazine, olanzapine, risperidone, ziprasidone, and quetiapine). Although the new generation antipsychotics seem to be more effective and appear to have a broader spectrum of action, they are far from being free of serious side effects (their nature, extent, and severity will be reviewed in site). Atypical antipsychotic medications have metabolic, endocrinological, cardiovascular, and even neurological side effects. Furthermore, second generation antipsychotics are very expensive. Atypicals appear to offer a better margin of safety regarding the risk of sudden death or other serious cardiovascular side effects.
From patients’ subjective perspective, the major obstacles to treatment, expressed by more than half of the patients interviewed in one study, are medication side effects. The latter not only affects the patient individually but may also have impact on the family: if the patient looks overmedicated or if he or she develops extrapyramidal side effects or Tourette’s disorder (and here we need to add: if the patient increases weight inordinately or if he or she displays signs of a metabolic syndrome), the family may not support the use of antipsychotics. Furthermore, according to Tandom, it is because of the atypicals’ extrapyramidal side effects advantage that patients get better cognition, less Tourette’s disorder, better compliance, and less dysphoria. If the extrapyramidal side effects advantage is lost, these benefits vanish. See commentary above.
There are only a handful of studies that demonstrate superiority of one atypical over others, and in these studies there are questions of methodology. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) a double-blind, placebo controlled, “head to head” study of chronic schizophrenic adults, was carried out utilizing olanzapine, risperidone, quetiapine, ziprasidone, and perphenazine; olanzapine demonstrated some therapeutic superiority over the other antipsychotics. Olanzapine had a longer staying power, reduced psychopathology to a greater degree, and was most effective in preventing relapse and rehospitalization, in comparison to the other antipsychotics. Different atypicals may not work in the same manner or may affect the brain functioning in different ways.
Some published studies are biased to sponsored company products, while other studies suffer from sample size, length of the studies, optimal therapeutic doses, statistical analysis, and/or a comprehensive survey of side effects. The manufacturers supported studies bias explains amusing paradoxes like the one reflected in the title article by Heres et al. (2006), “Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second Generation Antipsychotics.” In this study, the authors revealed a clear linkbetween sponsorship and study outcome; in 90% of the abstracts reviewed, results were rated as showing an overall superiority of the sponsor’s drug. Even more striking, different comparison of the same two antipsychotics led to contradictory overall conclusions depending on the sponsor of the study. It is progressively evident that second generation antipsychotic comparisons to first generation antipsychotics, like haloperidol, are lopsided in favor of second generation antipsychotics because haloperidol doses, when used as a comparator, are excessive, thus producing higher side effects rates (particularly, impact on negative symptoms and cognitive performance). These biases make the other antipsychotics appear more beneficial and more benign.
Most of the sparse references so far published, relate to short-term treatments; for a number of psychotic conditions, optimal therapeutic effects only occur after many months of antipsychotic treatment. The CATIE trial is the longest head-to-head, controlled study so far. Studies of long-term treatment outcomes and long-term side effects of atypical medications are lacking, particularly in children and adolescents.
Little is known about the interactions between psychotropic medications and the brain (Critical Breakthroughs, 2001). The same maybe said about the long-term effects of atypicals on other organ systems and on the human genome.
There has been a dramatic increase in the prescription of antipsychotic medications in recent years. Approximately 10% of all antipsychotic prescriptions written in the United States are for use in children and adolescents (17 years or younger). The majority of children who receive antipsychotic medications are in the 7 to 12 and 13 to 17 age groups, 43 and 47% respectively; 10% of those receiving these medications are under 7 years of age.
There are limited literature references available to guide the child and adolescent psychiatric clinicians in the use of antipsychotic medications, and atypical antipsychotic medications in particular: “In many ways, physicians treating these patients (children and adolescents) are becoming the pioneers of this emergent field” (Critical Breakthroughs, 2001).
Since knowledge of the mechanism of the therapeutic action and long-term side effects of atypical antipsychotics is lacking, we should look with concern at the rapid expansion of the use of these medications in children’s nonpsychotic conditions. At the present time the atypical medications are being used in a vast array of nonpsychotic disorders. It has been estimated that more than 75 to 85% of the atypicals are currently being used outside of the psychosis categories (off-off label). There are growing concerns with overprescription of medications in children, and with overprescription of antipsychotics, in particular: “Although close scrutiny suggests that most medications were prescribed appropriately, roughly two-thirds of all antipsychotics were prescribed for no psychotic conditions” (Clinical Breakthroughs, 2001). Atypical antipsychotic costs are enormous when compared with those of first generation antipsychotics. From a public health perspective, questions are being raised regarding the cost-benefit ratio. The CATIE report justifies a reconsideration of the role of first generation antipsychotics.
The increase in the prescription of antipsychotic medications for children and adolescents in the Texas Medicaid program from 1996 to 2000, has been unprecedented: “[T]here was a sizable increase of 494% in the prevalence rate of children and adolescents receiving atypical antipsychotics — a fact that reflects the growing acceptance of these medications by clinicians”, even though the safety and efficacy of these products have not been demonstrated in pediatric populations. “It is difficult to evaluate the long-term effects of atypical antipsychotics in children and adolescents, as these agents are relatively new to the market and few long-term studies have been performed… effects on learning and cognition as well as growth and development have yet to be determined”. There is reason to believe that the Texas experience is not an isolated one and that the broad use of atypical antipsychotics is widespread across the nation, and beyond.
Although, experiences in the use of antipsychotics in institutional settings are hardly generalizable to broader settings, it is still illustrative that in the “real world,” the adherence to preferred practices for the administration and monitoring of these medications is infrequently adhered to. These authors note, that among children and adolescent inpatients, atypical antipsychotics are mainly prescribed for aggression rather than psychosis (p. Ill), and that, for the treatment of aggression, antipsychotics are the most commonly prescribed agents across most inpatient settings. Only 9.7% of all diagnoses in the sample were psychotic in nature. Preferred practices are not followed in the use of antipsychotics and there was a lack of systematic monitoring of side effects and questionable polypharmacy, as well as a systematic lack of targeting of therapeutic effects. There is a dearth of evidence to support the current practices involving the use of antipsychotic medications to treat aggression in youth. A major concern related to the fact that neuroleptic treatment that begins in childhood may last a lifetime and may thus have incalculable neurological and functional impact. To these concerns we need to add the potentially detrimental effect that these medications have on weight gain and other metabolic effects, with implications for shortening the life span. Because of gaps in our knowledge regarding long-term safety and efficacy of atypical antipsychotics, controlled trials [particularly in children and adolescents] are urgently needed in this area. As reported by Gelenberg (2002),
[T]he Expert Consensus Guidelines for the Treatment of Schizophrenia recommended the new generation of antipsychotics as the treatment of choice in almost all cases of schizophrenia. Nonetheless, an estimated 20% to 25% of patients in United States, who take antipsychotics, still use first-generation agents. The consensus guidelines recommended “typical neuroleptics” in only three groups of patients: (1) stable patients who tolerate the older agents and have had a good clinical response; (2) patients requiring long-acting injectable preparations (although now, there are effective parenteral atypical alternatives, i.e., Consta, IM risperidone and Geodon IM); and (3) patients for whom only conventional antipsychotics sufficiently control aggression and violence,
To these, we add (4), patients who, for lack of health resources, cannot afford the more expensive atypical prescriptions. It is far better for some patients to receive medications with some added risks, than to receive no medications at all. See previous commentaries on the CATIE report, above. Questions regarding efficacy and safety of atypical antipsychotics, in children and adolescents, are still largely unanswered.