Tag: disease-centered model

04/21/20

Pros and Cons of Antipsychotics

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Antipsychotic treatment is often associated with weight gain and metabolic syndrome, a cluster of symptoms that increases the risk of heart disease, stroke and diabetes, independent of other adverse effects like sexual dysfunction, drowsiness, dizziness, restlessness, and others. In The Lancet, Pillinger et al compared and ranked 18 antipsychotics on the basis of their metabolic side-effects. They found that antipsychotics varied widely in their effects on body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and glucose concentrations. Olanzapine (Zyprexa) and clozapine (Clozaril) were ranked the worst for metabolic-related adverse effects, while ironically being identified as among the most effective antipsychotic drugs. Aripiprazole (Abilify, Aristada), brexpiprazole (Rexulti), cariprazine (Vraylar), lurasidone (Latuda), and ziprasidone (Geodon) were the most benign profiles.

In the same issue of The Lancet, Yoav Domany and Mark Weiser compared the results of this study with a network meta-analysis on the efficacy and adverse effects of antipsychotics. Clozapine was the most efficacious in reducing overall symptoms and amisulpride (Solian) was the most efficacious in reducing positive symptoms. “One would hope that data on efficacy and adverse events could be taken together with the detailed information on metabolic adverse events from this study to consider a personalized medicine approach in treating patients with schizophrenia.”

This approach could be part of a shared decision-making process, based on a discussion with the patient weighing the benefits and disadvantages of each treatment option. Such an approach is hampered by the fact that clozapine and olanzapine, which consistently come out among the best in terms of efficacy, are also consistently associated with the highest rates of metabolic adverse effects, hindering such a process at this stage.

One limitation of the Pillinger et al study was the studies in its meta-analysis were quite short, in the range of 2-13 weeks. The authors noted how randomized controlled trials are generally short and recommended that future studies should “examine antipsychotic-induced metabolic dysregulation in patients receiving long-term maintenance therapy.” Further, lifestyle and treatment factors (physical comorbidity, alcohol use, smoking, diet, exercise, and co-prescription of psychiatric—eg, mood stabilisers—or physical health medications—eg, statins or anti-glycaemic drugs) may have influenced metabolic outcomes. “Treatment guidelines should be updated to reflect differences in metabolic risk, but the choice of the treatment intervention should be made on an individual patient basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.”

Standard treatment guidelines are that antipsychotic medications should continue indefinitely after someone has experienced more than one psychotic episode. But according to Sandra Steingard, there is less agreement treatment guidelines after a single psychotic episode.  “Current guidelines recommend drug treatment for two to five years, the idea being that if a person remains well during that time, it might then be safe to stop the drug.” She said most psychiatrists assumed that by reducing risk of relapse you would improve long-term outcomes. But that assumption may not be correct. Not only are there risks of weight gain and tardive dyskinesia, antipsychotics seem to impair functional outcome. Robert Whitaker reported that Martin Harrow and Thomas Jobe did a long-term study of 200 psychotic patients. Patients who were off medication had better cognitive functioning and lower levels of anxiety than medicated patients. Patients on medication were more likely to be psychotic at follow-up. “Eighty-six percent of the medication-compliant patients were psychotic at the 4.5-year follow-up, compared to 21% of those who had stayed off antipsychotics. This dramatic difference remained throughout the study.” See the following chart.

Harrow also found that once patients who went off medication were stable, they were likely to remain stable for extended time periods. None of the stable, off-med patients stable at the 7.5-year follow-up relapsed in the next 7.5 years. Seventy to 90% of the unmedicated patients were working more than half time, compared to roughly 25% of the medicated patients. Those with milder disorders who continued taking medications had worse outcomes than schizophrenia patients who were off their medications.

Harrow discovered that patients off medication regularly recovered from their psychotic symptoms over time (2-year to 4.5-year outcomes), and that once this happened, they had very low relapse rates. At the same time, a majority of the patients on medication regularly remained psychotic, and even those who did recover often relapsed. Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.

Schizophrenia monotherapy treatment is not always effective, and some individuals receive additional interventions, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and psychological therapies. Ortiz-Orendain and others conducted a Cochrane review that compared antipsychotic monotherapy and combined treatment. The authors found low-quality evidence that combined antipsychotics improved the clinical response. The study indicated that more people who received combination therapy showed an improvement in symptoms. But there were no clear differences with other outcomes, such as relapse, hospitalization, adverse events, discontinuing treatment or leaving the study early. In her review of the Ortiz-Orendain et al study for The Mental Elf, Elena Marcus said it was a well conducted systematic review. However,

One of the main limitations of this review lies in the quality of included studies, with outcomes rated as low or very low quality which really questions our confidence in the reported estimates. There was a particularly high or unclear risk of reporting bias and attrition bias across studies and as authors included quasi-randomised trials there was a risk of selection bias in ~70% of studies. Whilst five studies were clearly quasi-randomised, for 39 studies there was not enough information to judge whether sequence generation was truly random, so the risk of bias here was unclear rather than high.

Users of antipsychotic medications also describe a distinctive experience, characterized by sedation, cognitive impairment, emotional blunting and reduced motivation. These are in addition to the various physical effects, including weight gain, sexual dysfunction and neurological consequences. Thompson et al described a synthesis of qualitative data about mental and behavioral changes associated with taking antipsychotics, and how these interact with symptoms of psychosis and people’s sense of self and agency. They found that neuroleptics interfered with people’s ability to carry out basic activities. But they also reduced the intensity of intrusive psychotic experiences and other symptoms, such as anxiety and insomnia.

Anything that changes our mental faculties is likely to impact on our sense of ourselves, and this is a common experience in relation to mood or experience-modifying agents. In the studies we reviewed, some participants felt neuroleptic-induced effects deprived them of important aspects of their personality; their drives, imagination or humour, for example. Others felt that by reducing the symptoms of psychosis, the drugs were able to restore them to a state in which they felt ‘themselves’ again. Similarly, some people were content to view themselves as having a disease requiring ongoing treatment, while others felt that taking neuroleptic medication symbolised a tainted identity. Schizophrenia or psychosis can disrupt people’s sense of self, and studies of personal recovery have described the importance of reconstructing a sense of self in a way that is distinct from symptom improvement. Therefore, although neuroleptics may effectively suppress symptoms, their effects can nevertheless be experienced as detrimental to sense of self and identity, with important implications for social functioning and achievement of life goals.

John Read and Ann Sacia of the University of East London surveyed 650 individual’s experiences with antipsychotics. Two-thirds (66.9%) of the participants said their experiences with antipsychotic drugs was more negative than positive, with 34.9% stating their experiences were extremely negative. Nearly a quarter (22.1%) of the participants said their experiences were more positive than negative, with 5.7% saying their experiences were extremely positive. The authors said at the point of prescription clinicians should provide a full range of information about antipsychotics, including potential benefits and harms, difficulties withdrawing, and information on alternative treatments, such as psychological therapies.

Implied in the above critique of antipsychotics is the view that psychiatric drugs are psychoactive substances in the same way alcohol or heroin are psychoactive substances. This is what Joanna Moncrieff refers to as the ‘drug-centered’ model of drug action. Conversely, the opening study by Pillinger et al seems to view antipsychotics according to a ‘disease-centered’ model of drug action. Moncreiff said the disease-centered model is borrowed from medicine and presents drugs through the prism of disease, disorder or the symptoms the drugs are thought to treat. The significant effects (or efficacy) are the ones the drugs exert on the diseased or abnormal nervous system. Any others are of secondary interest and referred to as above as side effects or adverse effects.

In contrast, the ‘drug-centred’ model suggests that far from correcting an abnormal state, as the disease model suggests, psychiatric drugs induce an abnormal or altered state. Psychiatric drugs are psychoactive substances, like alcohol and heroin. Psychoactive substances modify the way the brain functions and by doing so produce alterations in thinking, feeling and behaviour. Psychoactive drugs exert their effects in anyone who takes them regardless of whether or not they have a mental condition. Different psychoactive substances produce different effects, however. The drug-centred model suggests that the psychoactive effects produced by some drugs can be useful therapeutically in some situations. They don’t do this in the way the disease-centred model suggests by normalising brain function. They do it by creating an abnormal or altered brain state that suppresses or replaces the manifestations of mental and behavioural problems.

The above discussion suggests individuals being treated with antipsychotics should weigh the risks and benefits of the medication prescribed to them. They need to gather information on their medication, its potential side effects and then monitor how they respond to the drug. This is consistent with what Joanna Moncrieff called the drug-centered model of drug action. The Harrow study also indicated that the use of antipsychotics may not be the best long-term treatment protocol for schizophrenia. If you are using or considering the use of antipsychotics, weigh the pros and cons.

08/26/15

The Elephant in the Room

© tiero | 123rf.com
© tiero | 123rf.com

In 2006, Joanna Moncrieff asked why it was so difficult to stop psychiatric drug treatment? Received wisdom had answered that the difficulty arises from the underlying illness manifesting itself as the therapeutic effects of the medication becomes weaker. This presumes that the medications have disease-specific actions; that there is a disease-centered model of psychotropic drug action. But what if it had nothing to do with the original problem? Moncrieff suggested that problems experienced after psychiatric drug withdrawal were often related to the withdrawal process rather than the underlying condition. “If this is the case, then the recurrent nature of psychiatric disorders may be partially attributable to the iatrogenic effects of psychiatric drugs.”

She reviewed several case study examples to illustrate this concern and then indicated there were two possible mechanisms for withdrawal related disorders from this evidence. First, there were pharmacodynamic adaptations that took place. Long-term use of drugs that suppresses particular neurotransmitters (like serotonin in SSRIs) seems to cause an increase in number or a supersensitivity of the relevant receptors. When the receptors are no longer influenced by the drug, there is an over-activation of the neurotransmitter system—a rebound effect.

This may result in the characteristic discontinuation syndromes, may cause rapid onset psychosis and may act a source of  ‘‘pharmacodynamic stress,’’ which increases vulnerability to relapse.

A psychological reaction to the medication withdrawal, either by others or the patient, can also trigger symptoms or increase the patient’s vulnerability to relapse. Moncrieff said: “In my experience, psychological reactions by patients, staff and carers are important determinants of the success or failure of drug discontinuation, a proposition that is open to empirical testing.”

Moncrieff seems to be suggesting two things here. First, the importance of recognizing that post withdrawal symptoms will occur when a drug is tapered or stopped. Second, the importance of a system of support to the person seeking to successfully taper or stop their medications. Both of these factors are well known to anyone attempting to establish and maintain abstinence from addictive substances.

Along with David Cohen, Jonna Moncrieff suggested that we rethink our models of psychotropic drug action in their 2005 article. They noted the predominant “disease-centered model” of drug action that presumed psychiatric medications worked by acting on a specific disease process. In contrast, they suggested a “drug-centered model” that focused on the physiological, behavioral and subjective effects of the drug. Here, the therapeutic value of a drug stemmed from the usefulness of its effects in clinical situations. There is no presumption that it corrects some biological abnormality.

Moncrieff has also presented the differences between the disease-centered and the drug-centered models of drug action in her book, The Myth of the Chemical Cure. Moncrieff and Cohen used the distinction in a 2006 article, “Do Antidepressants Cure or Create Abnormal Brain States?” Applying the disease-centered model to antidepressants, they said:

Modelled on paradigmatic situations in general medicine—such as the use of insulin in diabetes, antibiotics in infectious disease, chemotherapy in cancer—the disease-centred model suggests that antidepressants help restore normal functioning by acting on the neuropathology of depression or of depressive symptoms.

Instead they proposed the drug-centered model was a better explanation for the observed drug effects in psychiatric conditions. “Instead of relieving a hypothetical biochemical abnormality, drugs themselves cause abnormal states, which may coincidentally relieve psychiatric symptoms.” After completing their analysis, they suggested that the term “antidepressant” should be abandoned, as the drugs were not treating a specific disease state.

Our analysis indicates that there are no specific antidepressant drugs, that most of the short-term effects of antidepressants are shared by many other drugs, and that long-term drug treatment with antidepressants or any other drugs has not been shown to lead to long-term elevation of mood.

This then brings us to “the elephant in the room”: a frank discussion on “The Psychoactive Effects of Psychiatric Medication” by Moncrieff, Cohen and Porter. They said when viewing the influence of psychiatric medications through the disease-centered model of action, their psychoactive effects have been obscured. “Despite six decades of intensive research in neuropharmacology … there is a lack of evidence that psychiatric drugs have a disease-specific action independent of their demonstrable psychoactive effects.” Approaching psychotropics as drugs that produce immediate and delayed psychoactive effects, with tolerance and dependence suggests that a radical change of thinking is needed.

Lessons from the use and misuse of other psychoactive substances can help to enlighten us about the broad range of behavioral effects that different psychiatric medications are likely to exert, and how these effects might interact with the psychological, behavioral, and other problems we call mental disorders.

Individuals who are prescribed psychiatric medications in this manner should be treated as consumers, “rather than passive recipients of diagnosis-driven prescribing.” The subjective experience of the individual would guide the use of psychiatric medications in a “collaborative dialogue” with the prescriber—rather than changes in symptoms or clusters of symptoms. “Only when we appreciate the nature of psychiatric drugs as psychoactive substances can we start to accumulate the knowledge necessary to enable prescribers and consumers to use these drugs safely and effectively.”

I heartily agree that we need to promote a drug-centered model of psychiatric drug action. However, additional changes will need to be made. Otherwise, the consumer-driven marketing model—“Ask your doctor if “X” is right for you”—will continue largely unchanged. Direct to the consumer advertising by Pharma will have to stop. Changes in how pharmaceuticals are approved though the FDA will have to occur. Better methodologies need to be developed for the approval process.

Transparency in pharmaceutical research needs to become the norm. Closer scrutiny into the potential harm and negative side effects has to occur, including long-term negative side effects. The psychoactive effect of drugs and its potential as negative side effect in all pharmacological products has to be weighed equally with the potential therapeutic benefit.

11/5/14

A Drug is a Drug is a Drug

lightwise / 123RF Stock Photo
lightwise / 123RF Stock Photo

“The modern understanding of what drugs do in psychiatry, the basis of psychopharmacology, is fatally flawed.” (Joanna Moncrieff)

In The Myth of the Chemical Cure, British psychiatrist Joanna Moncrieff persuasively argued that believing modern drug treatments are specific cures for specific illnesses “is just as mistaken as the belief that insulin coma treatment was an effective and specific treatment for schizophrenia.” This misperception has resulted in “the misdirection of research, the misinterpretation of available evidence and the obstruction of a fuller and more accurate understanding of what psychiatric drugs do.”

Essentially all of the drugs currently used in psychiatry have been developed since the 1950s. While drugs were widely used before that time, they were seen as having crude effects, “usually acting as chemical forms of restraint.” Since that time, drug treatment has been seen as making psychiatry “truly scientific.” Part of this transformation was a radical change in theories of what drugs actually do. “Instead of being seen as substances that induced effects that were crude but useful, they came to be seen as specific treatments for specific illnesses. They became ‘cures.’”

As a consequence, Moncrieff called the current view of psychotropic drug action the “disease-centered model.”  It exists in two related forms. One suggests that drugs act on the underlying causes of a disease or condition. The other suggests that drugs act on the specific pathology responsible for producing the psychiatric symptoms.

This disease-centered model is assumed and rarely articulated. But its existence can be inferred from the way that psychiatric drugs are described and investigated. The names of drug classes themselves reflect this disease centered-model: antipsychotics; antidepressants; anti-anxiety medications. It begs the question of exactly what the biological state is that these drugs are supposed to correct. “The predominant psychiatric theory about this is colloquially referred to as the ‘chemical imbalance’ theory of psychiatric disorder.”

Moncrieff proposed an alternative model, that she called the “drug-centered model.” It suggests that the therapeutic value of a drug is derived from the particular quality of the abnormal brain state it produces. “Psychiatric drugs are psychoactive drugs which, by their neurophysiological effects alter ‘mental and emotional life and behaviour for the duration of the treatment.’” Here is a reproduction of a table Moncrieff used in The Myth of the Chemical Cure to show the differences between the two models:

Disease-centered model

Drug-centered model

Drugs help correct an abnormal brain state

Drugs create an abnormal brain state

Therapeutic effects of drugs derive from their effects on presumed disease pathology

Therapeutic effect derive from the impact of the drugs-induced state on behavioral and emotional problems

Drug effects may differ between patients and volunteers

Effects do not differ

Outcomes of drug research consist of effects of drugs on measures of the ‘disease’ and its manifestations or symptoms

Outcomes are the global state produced by drug ingestion and how this interacts with behaviors and experiences

Paradigm: insulin for diabetes

Paradigm: alcohol for social phobia/social anxiety

Along with their immediate effects, when psychiatric drugs are taken over a long period of time on a regular and frequent basis, they “induce physical adaptations to the presence of the drug.” These adaptations can be understood as the body’s defense against the effects of a foreign substance and have several consequences. First, they counteract the immediate effects of the drugs, so that larger doses are needed to achieve the same effects. In other words, tolerance to the drug occurs. A second adaptation occurs:

When the drug is stopped or reduced, especially if this is done suddenly, the bodily adaptations are suddenly unopposed by the presence of the drug. It is these unopposed adaptations that cause withdrawal symptoms and they may cause other problems such as precipitating an episode of psychiatric disorder.

If this is interpreted through the disease-centered model, the bodily reaction is interpreted as evidence of the supposed reactivation of an underlying psychiatric condition, rather than a withdrawal syndrome resulting from the decreased presence of the drug in the individual’s body. In opposition to this understanding, the drug-centered model of drug action suggests the effects of drugs used in psychiatry work essentially the same way that recreational drugs do.

In the case of recreational use of drugs, it is effects such as euphoria, stimulation, indifference, disinhibition, psychedelic experiences and some types of sedation that are sought after. These effects are valued as pleasant in themselves, and also as ways of blocking out and anasesthetising people against painful memories and current difficulties. Drugs used in psychiatry have a similar range of effects, and several psychiatric drugs are also drugs of misuse.

I have to confess that while I’ve spent my professional counseling career working with individuals struggling with drugs of abuse, the disease-centered model of drug action encompassed my worldview of the so-called mental disorders for too long. This was despite knowing on some level that what Joanna Moncrieff said was true.

There is a saying in Narcotics Anonymous (N.A.) that applies to the drug-centered model for psychiatric medications introduced here: “A drug is a drug is a drug.” We have lived too long with the disease-centered model of psychotropic drug action. A drug is a drug, regardless of whether it is alcohol, cocaine, Prozac or Seroquel. Psychotropic drugs do not correct abnormal brain states; they create them. You can watch YouTube videos of Joanna Moncrieff here (The Myth of the Chemical Cure: The Politics of Psychiatric Treatment) and here (De-mystifying psychiatric drugs). You can also go to her website for more information. She’s even made some of her published papers available.