Psicofarmaci e violenza

violenzaNeuroleptic Drugs and Violence

 

Catherine Clarke SRN, SCM, MSSCH, MBChA.

and Jan Evans MCSP. Grad Dip Phys.

August 19th, 2012

Introduction

 

We address the fact that the treatment for Severe Mental Illness (SMI) is neuroleptic medication. One has to give significant thought about the involvement of neuroleptic medications with the tragic circumstances of individuals who have perpetuated a progressive catalogue of catastrophic actions, and the many victims and their families who so sadly are caught up in such tragedies.

 

It is established that there is an increased risk of violence by people with a mental health diagnosis. A greater risk of violent behaviour (27.6%) has been found for patients who commit substance abuse, compared to non-abusers (8.5%). For patients with schizophrenia, 13.2 % committed at least one violent offence, compared with 5.3% of the general population.1

 

Violence is reported with command hallucinations: 48% experienced harmful or dangerous actions and this increased to 63% in medium secure units and was significantly higher, 83%, in the forensic population.2

 

People who are classified as SMI i.e. with schizophrenia or bipolar often experience violent incidents following a diagnosis of SMI, even though they don’t consume alcohol or use street drugs, nor having a past history of violence or command hallucinations to harm others.

Our purpose of this document is to provide a referenced explanation of how neuroleptic medications are a potential cause of violence. We take a physiological perspective concerning pharmacogenetic variants and the disruption of neurotransmitters. In Part 1 we discuss what is known about Neuroleptics and Neurotransmitters; in Part 2, the Neuroleptic Disruption of Neurotransmitters

 

Part 1

 

The first part of this document has the following structure:            

·       Violence

  • Neuroleptic Adverse Effects on Behaviour
  • Serotonin Disruption
  • Noradrenaline/Norepinephrine Disruption
  • Acetylcholine Disruption including Neuroleptic Malignant Syndrome and Organophosphate Poisoning

·       Neuroleptic Withdrawal Adverse Effects on Behaviour

·       Neurotransmitter Functioning and Behaviour

·       Increased Prescribing of Neuroleptics as a Risk for Increased Violence

 

Violence

This is an important issue. In three acute psychiatric units in Australia it was reported: “58 % of the incidents were serious violent incidents.”3 In an attempt to address psychiatric violence in the UK, the National Institute for Health and Clinical Excellence (NICE) has a full clinical guideline: Violence. The short-term management of disturbed/violent behaviour in in-patient psychiatric settings and emergency departments.4 Although this addresses many issues, it omits the following potential causes of violence:

  • Neuroleptic medications – due to neuroleptic disruption of neurotransmitter circuits such as dopamine, serotonin, norepinephrine/noradrenaline and acetylcholine.
  • Pharmacogenetics – the issue of inefficient neuroleptic metabolising.

 

Adverse Effects on Behaviour of Neuroleptics

 

Neuroleptic toxic adverse reactions are related to behavioural changes such as akathesia, which is known to be a predisposing factor to violence5 and was formally recognised in the late 1970s.6

 

The symptoms of akathisia, an extreme, involuntary internal physical and emotional restlessness, includes restlessness, agitation and irritability.

 

When there is an existing precondition of akathisia, any perceived untoward disrespectful attitudes or verbal communications can trigger violence. When patients are agitated or irritable, they are less able to cope with perceived disrespect and are more prone to respond violently.

 

A marked increase of violence has occurred with patients prescribed moderately high-doses of haloperidol,7 and with Asian patients clozapine played a role in causing aggression and disruptive behaviour.8 Both the older ‘typical’ and the newer ‘atypical’ neuroleptics are associated with adverse behavioural reactions in a study reporting that “the newer antipsychotics did not reduce violence more than perphenazine.”9

 

Chart Depicting Toxic Behavioural Effects for Typical Neuroleptics:

 

 

Typical Neuroleptics

 

 

Adverse Reactions Related to Violence

Clopixol Agitation & akathisia
Haloperidol Restlessness, agitation and violence
Stelazine Restlessness
Sulpiride Restlessness & akathisia

 

 Refs 7, 10 &11

 

Chart Depicting the Toxic Behavioural Effects for Atypical Neuroleptics:

 

           

Atypical Neuroleptics

 

Adverse Reactions Related to Violence

Abilify Restlessness, agitation and akathisia
Amisulpride Agitation

Clozaril

Akathisia and agitation
Olanzapine Restlessness and agitation
Palperidone/Invega Akathisia and aggression
Quetiapine Akathisia and irritability
Risperidone Agitation
Sertindole Akathisia
Zotepine Akathisia

 

Ref 10

                       

Observations in prison have also associated neuroleptic treatment with increased aggressive behaviour. Inmates were better able to control their aggression until they were prescribed neuroleptics and then the aggression rate almost tripled.12

 

Neuroleptic Withdrawal Adverse Effects on Behaviour

 

There is also the issue of violence experienced during withdrawal. Irritability and agitation is reported in association with neuroleptic withdrawal,13 and a direct reference links akathisia following the withdrawal of a depot in an inpatient setting.14 Irritability, agitation and akathisia need to be recognised as reactions to neuroleptic withdrawal. 

In order to prevent violence in association with akathisia and withdrawal, this process needs to be undertaken by a professional or lay-person who understands the potential problems and can therefore guard against unwittingly appearing at all antagonistic to the patient.

Neurotransmitter Functioning and Behaviour

 

Fundamentally, human behaviour is determined by neurotransmitter functioning and “A rich literature exists to support the notion that monoamine (i.e. serotonin, dopamine, and norepinephrine) neurotransmitter functioning is related to human aggressive behaviour.”15

 

Dopamine, serotonin and all other neurotransmitter circuits are interdependent and any disturbance in one will result in an imbalance in them all, disrupting normal functioning. Jackson’s First Law of Biopsychiatry states:  “For every action, there is an unequal and frequently unpredictable reaction.”16

 

Chronic neuroleptic treatment causes unpredictable behavioural reactions due to dysregulation and disruptions between dopamine, serotonin and acetylcholine neurotransmitters.

 

Neuroleptics and Serotonin Disruption

 

Some neuroleptics are known as serotomimetic drugs, affecting serotonin receptors – some block the receptors and some make them more active. “There are 14 different types of serotonin receptors that may be targeted by neuroleptics, with risperidone, clozapine, olanzapine, quetiapine and clopixol especially affecting the serotonin 5-HT2 receptor.”17 

           

Mental status changes occur in Serotonin Syndrome. This is caused by neuroleptic drugs due to serotonin toxicity.

Animal research indicates that serotonin disruption is associated with increased violence. Reduced levels of a specific serotonin metabolite (5-HIAA) in cerebrospinal fluid has been linked with increased aggression in both dogs and male rhesus macaques18-19 and low concentrations of 5-HIAA in different cultures have been consistently reported to be associated with impulsive destructive behaviours, aggression and violence.20

 

Since “Impulsive violence is closely linked to serotonergic function and to several brain regions”21 and since impulsivity is also linked with both low and high serotonin levels it is difficult to know which of these changes play the most important role in treatment emergent violence.”17 

 

The reciprocal interaction between the dopaminergic and serotonergic systems disturbed by either dopaminergic blockers or serotonergic enhancers leads to the disruption of homeostasis.22 Although the serotonin system and its interactions with other neurotransmitters are complex and full information is difficult to find, there are clear research papers, which show that serotonin and aggression are related.

 

Chart depicting Neuroleptic Serotonin Disruption associated Adverse Toxic Behavioural Effects:

Akathisia Irritability
Suicidality

Violence

Arson Aggression
Violent Crime Self Destructiveness
Impulsive Acts Agitation
Hostility Violent Suicide
Argumentativeness

 

Ref 23 & 24

 

Neuroleptics and Noradrenaline/Norepinephrine Disruption

 

Neuroleptics affect the norepinephrine neurotransmitter and akathisia induction with haloperidol is known to be associated with increased noradrenaline turnover.25- 26

 

Neuroleptics and Acetylcholine Disruption

 

An important function of the acetylcholine neurotransmitter is the control of psychological defence mechanisms including fight or flight responses.  Such responses are impulsive and naturally include aggression and violence.

 

In varying degrees, all neuroleptic drugs have anticholinergic properties. This means that they block and cause disruption to the acetylcholine neurotransmitters. The body compensates and responds by making and releasing more acetylcholine.27

 

Acetylcholine Disruption and Increased Violence

 

Aggressive responses such as defensive rage and violence have been linked with excessive acetylcholine in animals28 –30 and a relative acetylcholine increase is associated with neuroleptic drugs due to the disruption of the dopamine-acetylcholine equilibrium.31-32

 

Since excessive acetylcholine is linked with aggression and violence in animals, it is likely that neuroleptic induced acetylcholine abundance triggers aggression and violence in humans.

Neuroleptic → Disrupted dopamine-acetylcholine equilibrium → Relative acetylcholine increase → Aggression/Violence.

 

Neuroleptic Malignant Syndrome and Organophosphate Exposure

 

Neuroleptic Malignant Syndrome (NMS) is an adverse effect of neuroleptics, a potentially fatal condition with up to 76% mortality rate.  Symptoms of NMS include aggression, agitation and violence.27 & 33 New research associates NMS with elevated acetylcholine.34

 

Organophosphate chemicals form the basis of many insecticides, herbicides and nerve gases. They block the action of the body’s acetylcholinesterase enzyme, which breaks down acetylcholine so it may be processed and recycled. Excessive acetylcholine accumulates in the nervous system if the action of this enzyme is blocked.

 

Prolonged and repeated exposure to Organophosphates results in Chronic Organophosphate-Induced Neuropsychiatric Disorder (COPIND) e.g. in farmers who handle pesticides, due to chronic Organophosphate Poisoning (OP). COPIND behavioural symptom changes include: Hostility, Anger, Aggression and Violence.35-36  Since OP results in excessive acetylcholine, which is linked with aggression and violence in animals, the behavioural changes in COPIND are highly likely caused by excessive acetylcholine.

 

The link between Neuroleptic Malignant Syndrome and Organophosphate Poisoning

 

The symptoms of NMS and OP are similar. In both NMS and OP the replication of symptoms is due to autonomic instability and stems from disruption of the acetylcholine circuits and transmitters of the Autonomic Nervous System, involved with vital involuntary functions.

 

Autonomic Instability includes profuse sweating, high blood pressure, low blood pressure, respiratory distress, drooling, urinary or faecal incontinence, increased and

decreased heart rate.27

Chart Depicting the Symptom Similarities of NMS and OP

 

 

Neuroleptic Malignant Syndrome

 

Organophosphate Poisoning

 

Autonomic nervous system disturbance Autonomic Instability

Aggression, agitation and violence

Aggression
Muscle rigidity Paralysis, Dystonia, Cranial nerve palsy and polyneuropathy                                                                                                                                                                   
Muscle breakdown Weak respiratory and limb muscles
Coma, alterations of consciousness Loss of consciousness
Confusion Dementia, psychosis, anxiety, depression
Fever Seizures

 

Refs 27 & 33

Conclusion: Organophosphates, Neuroleptics and Violence

 

Organophosphate Poisoning results in over stimulated acetylcholine neuro-circuits and systems. The action of neuroleptics is similar.  It is generally accepted that Organophosphate Poisoning results in behavioural changes including violence.

 

Despite research to show that neuroleptics are associated with disrupted acetylcholine, it is not yet generally accepted that neuroleptics are a potential cause of violence.

 

Antipsychotic/neuroleptic drugs have strong anti-cholinergic properties and long-term use causes behavioural changes, which replicate the same behavioural changes occurring in chronic Organophosphate Poisoning:  

 

“This adaptation (to psychiatric drugs – author input) replicates the effect of organophosphate poisoning whether by nerve gas, by insecticide, or by anti-Alzheimers pharmaceuticals by over stimulating acetylcholine circuits of the brain.”27  

 

Increased Prescribing of Neuroleptics

 

There has been a distinct increase in neuroleptic medications, prescribed as part of treatment for mental health issues.

 

In the UK between 1998 and 2010, Neuroleptic drug prescriptions increased by an average of 5.1% every year.37 Over twelve years, this is a total increase of 60%.

 

In England, the approximate number of neuroleptic and depot (injection) prescriptions used by outpatients:

2008 – 7.0 million

2009 – 7.3 million

2010 – 7.6 million

2011 – 7.9 million38

 

However, due to confidentiality, the data for the number of neuroleptic prescriptions in inpatient settings is not made available. So the actual total increase of neuroleptic prescriptions in the UK is unknown.

 

Increased Prescribing as a Risk for Increased Violence

 

 

As outlined above, neuroleptics are a possible cause of violence. With ever increased prescribing of neuroleptic medications, it is reasonable to expect an increased amount of violent behaviour amongst those with a severe mental health diagnosis.

 

Since neuroleptic prescriptions are increasing by 300,000 per year in the UK, it is hypothesized that the rise in violence for neuroleptic-treated patients will escalate, whether in the community or in acute wards, secure units, prisons or outpatient units.

 

Part 2. Neuroleptics and Pharmacogenetics

 

The second part of this document has the following structure:

  • Introduction to Pharmacogenetics regarding Neuroleptics
  • Pharmacogenetics and Ethnic Black Populations
  • Black Populations and Psychiatric Intensive Care Units
  • Black Populations, detention under the UK Mental Health Act and UK Community Treatment Orders
  •  Pharmacogenetics as an explanation for Black Over-representation in

Psychiatric Intensive Care Units, detentions within the UK Mental

Health Act and Community Treatment Orders

­­­­­­­­­­­­­­­

Introduction to Pharmacogenetics with regards to Neuroleptics

 

Pharmacogenetics is the science of how drugs are broken down and used – i.e. metabolised in the body, mainly in the liver, by the genetically diverse Cytochrome P450 (CYP450) enzyme system and other drug metabolising systems. There are many CYP450 variants that affect therapeutic efficacy and inefficacy of medications.

 

Extensive Metabolisers are efficient metabolisers, whereby side-effects do not build up. Poor Metabolisers are inefficient metabolisers that have no metabolising activity whatsoever; this means that drug toxicities do build up and cause side effects. Intermediate Metabolisers have approximately 50% drug metabolising capacity and produce lesser side-effects than Poor Metabolisers.39 Ultra Rapid Metabolisers/ Hyperinducers have higher than normal rates of drug metabolism; Those medications which are classified as prodrugs are inactive until metabolised in the body, therefore Ultra Rapid Metabolisers are at increased risk of drug-induced side effects due to increased exposure to prodrug active drug metabolites.40

 

Neuroleptic drugs are metabolised through CYP450 enzymes e.g.CYP450 1A2, 2D6 and 2C19. A single neuroleptic can necessitate a combination of CYP450 enzymes for metabolisation.

All SMI patients who are Poor and/or Intermediate Metabolisers of neuroleptics, and Ultra Metabolisers of neuroleptic prodrugs; e.g. paliperidone, the active metabolite of risperidone; will inevitably suffer neurological and behavioural changes due to toxicities incurred from the inability to metabolise neuroleptics efficiently. Polypharmacy compounds the toxicities.

 

CYP450 1A2 Metabolising Pathway and Neuroleptics

CYP450 1A2 enzyme pathway has many variants and metabolises olanzapine and haloperidol and is the major metabolising enzyme for clozapine.

 

CYP1A2*1C and *1D Poor Metabolisers have been associated with increased clozapine exposure and adverse reactions.41 CYP1A2*1K is also Poor Metaboliser genotype.42

 

In one study, Asian patients who were prescribed clozapine, experienced aggression and disruptive behaviour who, following clozapine discontinuation, had marked improvement.8 The genotype of the Asian patients in the study is unknown, however since 25% of Asians have CYP1A2*1C Poor Metaboliser genotype,43  it is possible these patients were either CYP1A2*1C, *1D or *1K or a combination of these Poor Metaboliser genotypes.

 

Additionally15-20% of Asians are Poor Metabolisers for CYP2C19 and 2% are Poor Metabolisers for CYP2D6.44CYP2C19 and CYP2D6 metabolise clozapine as well as CYP1A2; any of these combinations are possible and could have predisposed to disruptive behaviour.

CYP450 2D6 Metabolising Pathway and Neuroleptics

 

75% of all psychotropic drugs, including neuroleptics, are metabolised via CYP450 2D6.45 CYP450 2D6 is a highly variable enzyme with a significant percentage of the population being Poor, Intermediate or Ultra Metabolisers and is linked with a poor therapeutic response and adverse reactions.

 

Violence in relation with serotonin toxicity/akathisia has been linked with pharmacogenetic CYP450 2D6 drug metabolising variants.46

 

Pharmacogenetics and Ethnic Black Populations

 

Due to genetic variations there is higher incidence of Poor Metaboliser and Ultra Metaboliser status in Black populations, compared with White and Asian populations for the CYP 450 2D6 pathway. “The prevalence of poor metabolizers in Black populations has been estimated from 0 to 19%, compared with consistent reports of   poor metabolizer status in Caucasians (5–10%) and Asians (0–2%).”47

 

Recalling that 75% of neuroleptic medications are metabolised via CYP450 2D6, the following table shows the variation of metabolising ability in black ethnic populations for CYP450 2D6.

 

 

Poor Metabolisers

Ultra Metabolisers

South Africans

18.8%

Nigerians

8.6-8.3%

Ghanaians

6%

African – American

3.9%

2.4%

Zimbabwean

2%

Tanzanian

2%

American Black

1.9%

Ethiopians

1.8%

29%

 

Ref 48

 

29% of Ethiopians and 2.4% of North African Americans are Ultra Metabolisers via CYP450 2D6 pathway.48 Furthermore, 10-20% of Africans are Poor Metabolisers and 5% are Ultra Metabolisers via CYP450 2C19.49

 

Many prescription medications can lead to “serious mental change.”50 Since black populations statistically have difficulty in metabolising general and psychotropic medications and cannabis via the CYP450 pathways, this factor could contribute to  BME groups living in the UK who are more likely to be diagnosed with a Mental Health problem and admitted to hospital.51

 

 

Psychiatric Intensive Care Units and Over-representation of Black Populations

In UK Psychiatric Intensive Care Units (PICU), there is clear over-representation of black ethnic patients.52 Another study showed fifty-five percent of PICU admissions came from ethnic minorities(compared with 25.6% of total hospital admissions and 20.9%of the local catchment area population aged between 16 and 65years).53

“TypicalPICU patients are male, younger, single, unemployed, sufferingfrom schizophrenia or mania, from a Black Caribbean or Africanbackground, legally detained, with a forensic history. The mostcommon reason for admission is for aggression management.”54

 

UK Mental Health Act Detentions and Over-representation of Black Populations

There is also a disproportionately large representation of Black Minority and Ethnic (BME) origin when considering those who are legally detained under the UK Mental Health Act.

The proportion of black and black British people legally detained rose by 9.7%, with a 9% rise in the number of Asian or Asian British and mixed-race people detained for treatment, compared to a 0.3% rise for the overall number of people detained from 2007/8 to 2008/9. This disparity grew and 53.9% of black/black British inpatients spent time compulsorily detained, as did almost half of mixed-race inpatients and over 40% of Asian/Asian British inpatients, compared with 31.8% of all psychiatric inpatients who spent some time detained during the year.55

 

UK Community Treatment Orders and Black Populations

Legal UK Community Treatment Orders are enforced when patients have received mental health ‘treatment’ i.e. neuroleptics and history of violence; BME Groups have more Community Treatment Orders than white populations.56

“There is a possible relationship for psychiatric in-patients between compulsory detention, disturbed behaviour, depot medication and being black, which is not satisfactorily explained by diagnosis alone.”57

 

The higher incidence of mental health problems in black populations is most likely due to the higher incidence of Poor, Intermediate and Ultra Metabolisers and the associated problems with metabolising medications.

 

Synopsis

Neuroleptics can be a cause of violence due to neurotransmitter disruption.

 

Violence must be considered not simply as an indication of how deeply schizophrenia /bipolar illness can worsen, but as an adverse effect of neuroleptic treatment.

 

People who are inefficient metabolisers are likely to suffer more severe adverse effects and become violent or aggressive.

 

BME populations have a higher incidence of inefficient metabolisers and as such a higher incidence of violence leading to PICU admissions and Mental Health Act detentions.

 

However whatever the nationality, when individuals are Poor and Intermediate Metabolisers and Ultra Rapid Metabolisers for prodrugs, the impact of neuroleptics in triggering akathisia, aggression or irritability can trigger violence indiscriminately.

 

Conclusion

There is a larger incidence of violence in people with a severe mental health diagnosis than in the general population. The severely mentally ill are invariably treated with neuroleptic medication which itself can be the cause of violence since neuroleptic medications disrupt neurotransmitter functions. This disruption of neurotransmitter functioning can precipitate violent behaviour. Withdrawal of neuroleptic medication – due again to the disruption of neurotransmitters – is also associated with violence.

 

Pharmacogenetics show that the some people are unable to metabolise neuroleptic medication and this inability can result in further disruption of neurotransmitter functioning with a likelihood of increased violence.

The inability to metabolise neuroleptic medication is particularly prevalent in BME populations. As a consequence this population experience more violence which is confirmed in practice by an over representation of BME individuals, both on Psychiatric Intensive Care Units (PICUs) where a common reason for admission is aggression, and the use of Mental Health Act detentions and Community Treatment Orders.

 

With the trend towards increased prescribing of neuroleptic medications, a level of increased violence can be anticipated for the future.

 

There is the possibility of ameliorating the presence of violence in the severely mentally ill by ensuring pharmacogenetics is more fully recognised as a significant factor, and that genotype testing is adopted in order to assess the ability of the individual to metabolise neuroleptic medication. Without this testing,

much of the violence in psychiatry can be laid at the door of  psychiatrists and the  pharmaceutical companies.

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Ref 57 Violence: The Short-Term Management of Disturbed/Violent Behaviour in Psychiatric In-patients and Emergency Departments Guideline, Appendix 1: Ethnicity review evidence tables. p.447 http://www.rcn.org.uk/__data/assets/pdf_file/0003/109812/003017_appendices.pdf

 

 

 

 

 

 

 

 

 

 

Gli antidepressivi come i placebo

SSRI

New Research on the Antidepressant-vs.-Placebo Debate

(Updated) In the 1990s, everyone was “Listening to Prozac,” after best-selling author Peter Kramer described sparkling personality transformations in patients who took the titular antidepressant drug. Then came the backlash: by the early 2000s, studies showed that Prozac and other selective serotonin reuptake inhibitors, or SSRIs, weren’t exactly miracle pills but were instead associated with suicide, especially in kids and teens. Another whiplash-inducing turn came in 2008, when a review of the research found that the drugs were actually no more effective than sugar pills, except in cases of the most severe depression.

Last month, research published in the Archives of General Psychiatry sought to help explain the paradoxical findings on SSRIs and other new generation antidepressant drugs, the increasingly popular medications that are now used by more than 1 in 10 Americans over 12. Using a new statistical approach, researchers led by Dr. John Krystal at Yale University School of Medicine reanalyzed data from seven clinical trials involving 2,515 patients, whose results were used to win FDA approval for the SNRI (a drug that affects both serotonin and norepinephrine) duloxetine (Cymbalta).

Known as growth-mixture modeling, the statistical technique allowed the authors to track how individual patients improved or worsened over time in response to medication or a placebo. The researchers found that roughly three-quarters of patients did better on medication than on a placebo. “That’s much more than half and half. That’s quite favorable,” says Krystal.

However, Krystal adds, just under a quarter of patients did not respond well to drug treatment and in fact did worse on antidepressants than did patients who were given a placebo.

MORE: Report: 1 in 5 American Adults Takes Mental Health Drugs

The benefit of growth-mixture modeling is that it reveals treatment trajectories of patients rather than looking at outcomes on average. When some patients get better while others get worse, the true impact of the drug may be “canceled out” in the data if they are considered only in the aggregate, obscuring both the drug’s harms and its benefits. That may help explain why some research finds that antidepressants work no better than a placebo.

“This has enormous implications for understanding the limits of the effectiveness of our current medications,” says Krystal. “These data really caution against the demonization of antidepressants as merely placebo, but they do raise a concern that some people are better off on placebo than on the antidepressant that they’re getting.”

Irving Kirsch, professor of psychology at the University of Hull in England and author of a 2008 meta-analysis in PLoS Medicine that found little benefit of antidepressants for most patients, is less sanguine about the new study. He characterizes the results as “indeed important” but says they suggest that “while many people may benefit from antidepressant treatment (although most of them to a degree that is not clinically significant), about 1 in 4 are made worse.”

“What makes this particularly problematic is the fact that we don’t know who these people are,” Kirsch says. “Although placebo may not be a viable treatment option, there are other treatments that on average work as well as antidepressants, [such as] physical exercise and cognitive behavioral psychotherapy. As far as we know, these alternatives don’t make people worse.

“This suggests to me that antidepressants should be kept as a last resort, and if a person does not respond to the treatment within a few weeks, it should be discontinued,” says Kirsch.

Krystal agrees that if one-quarter of patients with depression are made worse by antidepressant treatment, “we need to find ways to identify who those people are and find other ways to reach that group of people.”

MORE: Study Shows Antidepressants Affect Brain Differently than Placebo

Krystal’s study also found that people who improved on a placebo did so as quickly as those who improved with medication. This is important because it suggests that using a “washout period,” a technique used in some clinical trials to weed out placebo responders by eliminating participants who respond quickly, may not work with antidepressant studies.

“It counteracts the expectations that the field has that placebo response is fast and drug response is slow. Simply having a brief placebo-exposure period is not likely to eliminate the impact of placebo on outcome,” Krystal says.

That further complicates efforts to figure out the true effects and mechanism of antidepressant drugs. “We’re going to have to study people who are worse off on drug than placebo, and [not knowing who they are] will make it harder to determine whether there’s a statistically significant effect of the drug.” And given that it may be difficult to eliminate placebo responders simply through clever study design, questions about how antidepressants work, and in whom, may not be resolved until genetic or other tests can be devised to predict individual responses.

“This going to remain a challenge for study for some time,” concludes Krystal, whose latest study was funded by the government but who has received industry funding for other research.

MORE: Study: Stress-Depression Connection Sheds Light on Antidepressant Effects

A separate study published in the American Journal of Psychiatry (AJP) in December highlights other potential complications. The authors of that paper report that since 1980, the percentage of depressed patients responding to a placebo in clinical trials has risen by 7% per decade, reaching 50% in some studies.

Why? In the early years, participants for antidepressant trials were recruited from psychiatric hospitals, which meant that only the most severe cases were included. Today, however, participants are often recruited through advertisements and are paid to be in the trials. That introduces two problems that skew study populations: the most seriously depressed people often lack the capacity even to make a phone call in response to an ad and are thus overlooked, while other people may be persuaded to exaggerate symptoms of depression in order to participate in the trials and get the money. The authors of the AJP study report cases of “professional guinea pigs” who faked symptoms or enrolled in several trials at once.

Given the complexities of studying antidepressants — which appear to be placebos for some, poisons for others and miracle pills for yet others — it seems that data analysis in antidepressant research will likely remain a growth industry for decades to come. Until scientists can work it out, patients and psychiatrists will have to try multiple methods to treat depression until they hit on something that helps, keeping in mind that antidepressant drugs may backfire for some patients.

MOREWhy American Presidents (and Some Oscar Winners) Live Longer

Correction [Jan. 23, 2012]: The original version of this story mischaracterized Cymbalta as a selective serotonin reuptake inhibitor, or SSRI. The antidepressant drug is an SNRI, which affects both norepinephrine and serotonin.

Maia Szalavitz is a health writer for TIME.com. Find her on Twitter at @maiasz. You can also continue the discussion on TIME Healthland‘s Facebook page and on Twitter at @TIMEHealthland.

Read more: http://healthland.time.com/2012/01/18/new-research-on-the-antidepressant-versus-placebo-debate/#ixzz2Jdn2N6Ft

The shooters

Film Title: ShooterShooters

Steven Taylor

Several writers of my acquaintance, such as Allen Ginsberg and Ed Sanders, developed the habit of keeping extensive files of press clippings on stories of personal interest. Noam Chomsky, we’re told, does the same thing. An individual news report may mention something in passing that may seem secondary to the main narrative, but when multiple stories collected over time repeat the same seemingly secondary data, important patterns can become apparent.

For example, for many years Ginsberg clipped New York Times articles having to do with the international traffic in narcotics. This collection eventually served as one of the sources for historian Alfred W. McCoy’s definitive study linking the heroin trade to U. S. government agencies, The Politics of Heroin.

Now, amid the sickening media parade endlessly looping, one aspect of the mass shooter phenomenon is continually skipped, but a survey of press reports on the spate of bizarre violence that has arisen since the 1990s reveals a pattern.

In the past few days, following the Newtown murders, various experts have weighed in on the difficulty of profiling the mass shooter type. (An accurate psychological profile, presumably — and hideously problematically — could enable parents, teachers, doctors, and law enforcers to predict which individual is headed toward being the next shooter.)

Despite the difficulty of such profiles and predictions, there are two things that such characters have in common. First, they are mostly young white males. Second, many of the perpetrators are reported to have been taking psychoactive prescription medication.

The website “SSRI Stories: Antidepressant Nightmares” offers a sortable database of more than 4,800 newspaper articles, scientific journal reports, and TV news items linking antidepressant use to cases of extreme violence.

It is important to note that this site is not peddling some conspiracy theory. It is not speculative at all. The website is an index to reputable sources reporting on actual criminal cases, and in all cases reported, prescription meds are implicated.

The articles show that these violent acts were perpetrated by consumers in the 50 billion dollar a year selective serotonin reuptake inhibitor (SSRI) industry. This is a class of drugs whose warning labels and pharmaceutical literature note that a small percentage of SSRI consumers fantasize about and/or exhibit extreme violence.

I was originally tipped to this in July of 2012 in an article by RS regular Jonathan Zap, which he wrote in the wake of the so-called Batman shootings of that summer.

Zap notes as follows.

“Mass shootings, like the one that just happened in Aurora [Colorado], have become a recurrent nightmare that haunts the collective psyche. As the nightmare repeats, we see patterns emerging. One, which we don’t have confirmation on yet in this case, is that the shooter will almost always turn out to be on an SSRI (selective serotonin reuptake inhibitor). For example, Colorado’s other most famous mass shooting, Columbine, was masterminded by 18-year-old Eric Harris who was on the SSRI medication Luvox. Here’s an index of shootings and the SSRI connection someone put together.”

The website Jonathan links us to, “SSRI Stories: Antidepressant Nightmares,” concentrates on reports implicating Prozac (the FDA’s number 2 drug for violence), Zoloft, Paxil (number 3 for violence), Celexa, Lexapro, Luvox, Remeron, Anafranil, Effexor, Cymbalta, Pristiq, and Wellbutrin.images

Here are a few samples of reports from the site, with comments.

“Tim Kretschmer . . . walked into Albertville Secondary in Winnenden, near Stuttgart, at 9.30am on Wednesday armed with a 9mm Beretta he had stolen from his gun enthusiast father and wearing a K4-Schutz bulletproof vest and the black fatigues of Germany’s elite forces, the Kommando Spezialkräfte. . . . He killed nine pupils at Albertville, all but one a girl, and three teachers, all women, in less than 10 minutes. He then shot and killed three bystanders as he tried to escape, before taking his own life after a shootout with police. . . . It emerged that Kretschmer had been suffering from depression . . . and receiving medication for the condition.” –Scotland On Sunday, Edinburgh, March 14 2009.

“Hours before he walked into a Northern Illinois University lecture hall and inexplicably started a shooting rampage that ended five lives and his own, Steve Kazmierczak called one of the people he was closest to and said what would be a final goodbye. . . . [According to his girlfriend] ‘he was anything but a monster. He was probably the nicest, most caring person ever’. . . . [She said] he saw a psychiatrist monthly but stopped taking Prozac a few weeks ago. She said the medicine ‘made him feel like a zombie’.” –Chicago Sun Times, February 8, 2008.

What we might call the “zombie effect” seems to come up in many of these cases. Also common is that the violent behavior tends to occur when the patient is either having the dosage adjusted, or has just stopped taking the pills.

SSRIThe “SSRI Stories” site notes the following.

“The danger of withdrawal from antidepressants and antipsychotics is well documented. The brain tries to compensate for the blockage of the serotonin and dopamine receptors by growing additional receptors for these neurotransmitters. When the medications are discontinued, these additional receptors contribute to an ‘overload’ of serotonin and dopamine flooding the receptor. This is known as ‘supersensitivity psychosis’ and ‘antidepressant discontinuation syndrome’.”

“BEMIDJI, MINN. — Jeffrey Weise had ‘a good relationship’ with the grandfather he shot and killed on Monday as prelude to his deadly assault on students and others at Red Lake High School, according to relatives who are struggling to understand what might have pushed the teenager from sometimes bizarre behavior to mass murder and suicide. . . . They wondered, too, about medication he was supposedly taking for depression, and a recent increase in his prescribed dosage. . . . 60 milligrams a day of Prozac.” –Star Tribune (Minnesota), March 24, 2005.

Consistent with the “zombie effect” noted above, many sources indicate that some perpetrators who survive their crime scenes report being in a dreamlike state in which they feel they are watching their actions but not in control of them. Some of the literature notes sleep disorders, and speculates that the drugs induce a state of waking dream in which one becomes a passive witness to one’s actions. (Christopher Pittman, who killed his grandparents and set fire to their house told his father afterward that it had been like watching a TV show.) Other sources say the shooters do not remember their crimes or do not associate themselves with what occured.

“Huntsville, AL. — 15 year old Hammad Memon is free on bond, awaiting trial on murder charges for the February 2010 shooting death of fellow Discovery Middle School student Todd Brown. . . . Memon has a history of being treated for Attention Deficit Hyperactivity Disorder and Depression. He was being medicated with Zoloft and other drugs for the conditions. . . . Memon’s mother is quoted as saying ‘My son is not normal. He is immature (mentally) for his age. He has become very depressed and withdrawn for the past 2 years, especially in the last 12 months. He does not have insights into what crime he has committed’.” –The Free Republic (Alabama), Feb 5 2012.

“CARTHAGE, NC — Jurors in the Robert Stewart murder trial reached a verdict Saturday. He was found guilty of eight counts of second-degree murder in a shooting rampage at a North Carolina nursing home in 2009. . . . Stewart’s defense lawyers said the 47-year-old was essentially sleepwalking at the time due to taking a combination of prescription drugs. . . . Defense attorney Jon Megerian said Ambien and other drugs in Stewart’s system caused him to be in a zombie-like state of mind when he entered the nursing home. . . . In pleading Stewart’s case, his defense said he was full of remorse, but couldn’t remember anything. –WTVD television, North Carolina.

There have been a number of cases where defendants have been found not responsible for their actions due to the effects of the medication.

“STAMFORD, CT — A Stamford lawyer who shot at a motorist, then broke into his ex-wife’s house was found not guilty by reason of mental disease or defect yesterday. Eric Witlin, 40, will be committed to Whiting Forensic Institute for evaluation until he returns to court July 14. Judge Richard Comerford could commit Witlin for the time he could have been sentenced to prison, a total of 70 years. . . . Two psychiatrists, including one hired by the prosecution, testified that Witlin suffered a psychotic episode brought on by Adderall and Prozac, which were prescribed to treat attention deficit disorder and depression. . . . Senior Assistant State’s Attorney James Bernardi said Witlin’s mental state on the night of the incident was uncontested, since both psychiatrists agreed. –Stamford Advocate, May 20, 2008.

“Anna L. Tang, the troubled former Wellesley student, is finally free to resume her life and has been discharged from court custody. . . . Tang came to the attention of most MIT students in October 2007 when she stabbed her ex-boyfriend, Wolfe B. Styke, then a freshman, in his Next House dormitory room. . . . Tang has bipolar disorder, which she sought help for when she first arrived at Wellesley in 2005. At that time, she was diagnosed with depression and was prescribed an antidepressant. However, as Tang’s psychopharmacologist Michael J. Mufson testified during the trial, bipolar disorder cannot be treated with antidepressants. Doing so creates oscillatory behavior. ­ ‘It made her lows lower and her highs get higher’, Mufson said. That combination of misdiagnosis and mistreatment led to her attack on Styke. Judge Henry found in December that Tang lacked the substantial capacity to conform her actions to the requirements of the law and that she lacked the capacity to appreciate the wrongfulness of her actions. The Tech (MIT student newspaper), Feb 8, 2011.

In other legal news, there have been some 450 suicide-related lawsuits settled out of court by GlaxoSmithKline, the maker of Paxil.
“Since Paxil came on the market in 1992, there have been three separate types of failure to warn lawsuits filed: birth defects, suicide, and addiction. Roughly 150 suicide cases were settled for an average of about $2 million, and about 300 cases involving suicide attempts were settled for an average of $300,000, according to a December 14, 2009 report by Bloomberg News. Glaxo paid an average of about $50,000 each to resolve about 3,200 cases linking Paxil to addiction problems. . . . All total, Glaxo has paid out close to $1 billion to resolve Paxil lawsuits since the drug came on the market in 1992. The company’s provision for all legal matters and other non-tax disputes as of the end of 2008 was listed as $3.09 billion in its annual report.” –Dissidentvoice.org.

To summarize, FDA warnings, court finding, and too many news reports to count make a connection between one of the most widely prescribed drug types and bizarre, ostensibly “inexplicable” violence. And though there are thousands of sources and multiple vectors of association implicating the 50-billion-dollar business in SSRIs to some of the most hideous crimes of our day, the major media continue to spin their wheels about the “unexplainable.” This story needs to go viral. Now.

Image by Carsten Achertzer, courtesy of Creative Commons license.