Moncrieff et al.’s (2009) intro (an overview):

Antipsychotic drugs are being prescribed with increasing frequency to people with an expanding variety of diagnoses (1). Although, their physical effects have been well characterized, their subjective effects, in particular the mental alterations they produce, are less well recognised. Their mechanism of action has also not been clarified. Early investigators noted the striking ability of the first such drugs to produce a subjective state characterized by mental slowing, apathy and emotional indifference (2, 3). Subsequent studies with volunteers and first person accounts by patients also emphasize the emotional detachment, reduced initiative, dysphoria and akathisia produced by these drugs (4–7). Over the years, various labels have been used to describe these effects, including  “neuroleptics induced dysphoria” (8), “akinetic depression” (9),”neuroleptic induced deficit syndrome” (10), and “behavioural toxicity” (11, 12).

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The Israeli researchers Belmaker and Wald’s (1977) letter to the editor of the British Journal of Psychiatry reporting their personal experiences of haloperidol:

“Haloperidol is an effective antipsychotic agent which is a relatively specific blocker of dopamine transmission in the brain (Anden et al, 1970). As part of the preliminary trials in a study of possible dopaminergic mechanism in affective disorder, the two authors each were given haloperidol 5 mg intravenously in a two-minute push. The effect was marked and very similar in both of us: within ten minutes a marked slowing of thinking and movement developed, along with profound inner restlessness. Neither subject could continue work, and each left work for over 36 hours. Each subject complained of a paralysis of volition, a lack of physical and psychic energy. The subjects felt unable to read, telephone or perform household tasks of their own will, but could perform these tasks if demanded to do so. There was no sleepiness or sedation; on the contrary, both subjects complained of severe anxiety.

The present experience was similar to that previously reported of neuroleptic effects in normal subjects (DiMascio et al, 1963; Heninger at al, 1965), though previous studies used neuroleptics which block both dopamine and noradrenaline receptors (Anden et al, 1970).We used a relatively specific dopamine blocker, haloperidol, and experienced profound cognitive and emotional restriction. Dopamine blocking by neuroleptics may function to restrict cognitive and emotional processes in normals as well as in schizophrenics and thus it is possible that it does not specifically antagonize schizophrenic pathology. In the presence of psychotic anxiety or delusions, such cognitive or emotional restriction may be desirable and therapeutic. However, the restrictive effect may be a general one…”

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Excerpts from Healy and Farquhar’s (1998) study of droperidol (a dopamine antagonist) in normal subjects:

Akathisia

Droperidol, in this dose under these circumstances, induced restlessness in all 20 subjects. All subjects reported great difficulties with the completion of the tests. The tests it should be noted are boring. The levels of impatience experienced, however, were marked with some subjects remarking that they became belligerent or felt like putting a boot through the computer screen. Such reactions were out of character and were not reported in either the placebo or lorazepam groups. Fifteen of the 20 tested reported a mixture of reassurance by and irritation with the presence of the experimenter.

Sedation

Seventeen of the 20 subjects felt, in their words, sedated. Seven snoozed during the breaks between testing sessions, some feeling unable not to. Ten went to bed immediately on returning home that afternoon or early evening. Some slept successfully at that point, but others, owing to restlessness, did not. It was difficult to tease apart a proper sedative effect of the droperidol from the feeling of boredom in the test situation, but also from the feeling that things had become more effortful. Some subjects felt tired at the prospect of doing things and felt that they might not have been feeling sedated if the sense of effortfulness were lifted. There is a question, therefore, about the nature of this ‘sedative’ effect or the number of its component parts.

Dysphoria

Eleven subjects reported dysphoria while the other nine were quite sure that although akathisic, they were not dysphoric in any meaningful sense of that word. The onset of dysphoria in most cases was relatively immediate with one subject breaking down in tears within an hour of having droperidol. In part dysphoria appeared to mean an experience during the testing session that personal horizons were closing in. Another component appeared to stem from an anxiety that the state was likely to go on forever. Yet another component seemed to stem from the effort they were now having to make even to do the most simple things; they found this tremendously dispiriting and worried that everything would take a comparable effort in the future. Some of these subjects found themselves remembering some of the unhappiest moments in their life, perhaps owing to state dependent effects.

Other

Six subjects had very obvious ‘freezing’ responses during the course of the testing sessions. Images would flash up on the computer screen that required a response, but the subject was left looking at the screen and did not respond. This immobility was experienced by subjects as a lack of caring about the outcome. There was a general feeling common to all subjects to some extent of disengagement – a feeling of uninvolvement with tasks in hand. While feeling disengaged and uninterested, a number of subjects reported what appeared to be a paradoxical heightening of visual or auditory perceptions.

Mental effort appeared to be difficult, with all subjects reporting some problems with concentration. Apparently simple tasks, such as obtaining a sandwich from a sandwich machine, proved too difficult for some people, which contributed in turn to the dysphoria mentioned above.

“Sedation and mental clouding are of concern to people on antipsychotic medication and are implicated in social withdrawal but their severity may be underestimated by psychiatrists. Existing studies of communication about adverse effects of medication are based on reports made by doctors or patients. This study is based on audiotapes of 92 outpatient consultations in two UK mental health trusts involving nine consultant psychiatrists where antipsychotic medication was discussed. When interviewed, these doctors and their colleagues had expressed a commitment to ‘patient-centred’ practice as well as recording concerns about the difficulties involved in the discussion of medication side effects. The study focuses on the ways in which sedation and mental clouding are presented and engaged with. Analysis of audiotape transcripts showed that patients raise these issues more often than doctors, contrasting with other adverse effects (such as blood changes) where doctors are more frequently the initiators of discussion. Sleepiness is sometimes presented by both patients and doctors as a part of normal experience and therefore to be welcomed. When presented as troublesome, patients’ reports were sometimes met by doctors offering no response, changing the subject, or disagreeing with the patient’s interpretation of the experience. Equally, there were some attempts by doctors to engage with patients’ troubles and seek solutions. These could be unsuccessful where they involved challenges to the patients’ medication-taking rationale, or more successful where they involved sympathetic and supportive listening. We speculate that the capacity to avoid addressing these problems is linked to the informal conversational style of these consultations, which means that concerns raised by one party can remain unaddressed without offending conversational norms. Doctors in these consultations are able to exercise considerable discretion over whether to define reports of sedation and mental clouding as medication-related problems.”

“Psychiatrists differ from patients in their judgements of the distress caused by adverse effects of antipsychotic medication (Day, Kinderman, & Bentall, 1998; Rettenbacher, Burns, Kemmler, & Fleischhacker, 2004). Psychiatric perspectives on sedation and mental clouding may suffer particularly from this. For example, in their study of the information given by psychiatrists to patients about the side effects of antipsychotic drugs, Smith and Henderson (2000) listed 23 experiences that the authors (both psychiatrists) considered to be common adverse effects of these medications, without including sedation, drowsiness or mental clouding. Yet in a survey of patients reported by the National Schizophrenia Fellowship (2001a) where 2222 respondents were asked ‘What is the worst thing about taking medication for mental illness?’ ‘Sedation and lethargy’ was the most commonly mentioned ‘worst thing’ (22% of respondents).”

Patient excerpt from Rogers et al’s (2008) qualitative study of the subjective experience of medication adherence in subjects with schizophrenia:

“Well you just sort of, you’re walking around like a zombie and you’re like sort of you can’t join in with things, I wouldn’t be talking to you like what I’m talking now. I know I might seem a bit high, but when you’re on [the antipsychotic drug] you can’t even be bothered holding a conversation you know, you’re justsat there saying yes or no, so I won’t take it I’m sorry but I’m not taking it.”

“To me its a vicious circle, you’re either taking the tablets and feeling drugged up or you’re just bloody hearing the voices and freaking out at people you know.”

“I mean to be honest, you know chemicals, I don’t like the sort of stuff running through your blood, you know, and like feeling doped up and that. I’ve had it since I was thirteen and I’m thirty two now so I’m sick of it you know, and I know I could just tell them to sod off you know but if I really needed help, if I really got ill, they wouldn’t be there.”

“If I mentioned it, if my psychiatrist knew you know that I take herbal remedies, he’d just put my medication up, he’d think it was a sign of illness. Its not you know, its common sense… It’s a waste of time a waste of time you know talking to, you know, I can’t really talk to my doctor about it because he sees me as a schizophrenic you know, and you haven’t really got a mind of your own.”

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Patient comments from an internet content analysis by Joanna Moncrieff and colleagues reporting subjective experiences of a variety of older and newer antipsychotics:

I’m still fatigued in the morning and can barely get out of bed some days_ (T144)
I feel tired all the time. Too tired to be depressed_ (R316)
I was sleeping over 14 h a night and was so hung over during the day I could hardly go about my normal routines. I couldn’t even get myself dressed to go out to the store_ (O235).
low ability to make decisions_ (T146)
no thoughts or inner world_ (R356)
mental fogginess all the time_ (R1)
altered mental state, cannot focus. Impaired judgement and thinking_ (R372)
blank mind_ (O89)
sluggish thinking_ (O112)
loss of wits_ (O276)
I feel absolutely nothing!! No sadness, no joy, NOTHING_ (H119)
emotionally empty, dead inside… took away my sense of humour_ (T150)
oblivious to my surrounds….all creativity was squashed_ (T145)
no emotions, only a weird, spacey, empty feeling, no arousal, no excitement, no joy, nothing_ (R22)
total shut down of my outgoing personality_ (R181)
emotionless zombie_ (R392)
lack of interest in life, no will to carry on living_ (R16)
too zoned, too robotic, emotion dead_ (O97)
lost of emotions and general feeling that everything doesn’t matter at all_ (O234).
personality is dampened_ (O107).
general lack of interest in anything_ (O291)
extremely hard to move, think, talk_ (H121)
I feel like a zombie, I can’t think clear and my movement is slow_ (119H)
heavy mental and physical stagnance… retarded feeling_ (H137)
I felt like I was in slow motion_ (R21)
I am not able to think properly and am experiencing the world at about half the normal pace…Can’t keep my mind focused and my eyes are slow_ (O114).
mild inhibited feeling_ (O292).

Goff–who is much more appreciative of R and K’s work than Meltzer–questions the attribution of tardive dyskinesia to D2 blockade (referencing his own and others’ work on the role of glutamatergic excitotoxicity and oxidative stress) but nevertheless underscores that TD alone is only one aspect of potential AP-induced neurotoxicity.  Unresolved questions as to the causes of various iatrogenic changes in brain structure and function remain.  Goff also points to the problem of the highly variable (sometimes quite prolonged) “delay before relapse following drug discontinuation” in psychosis patients.  Is this delay due to the “persistence” of antipsychotic effects in certain individuals but not in others, or is psychosis/schizophrenia “naturally” more or less episodic in specific sub-groups?  Finally, what ‘biochemical changes’ are involved in relapse or symptom exacerbation across schizophrenia patients and how might an answer to these questions help us determine the best medication strategies for specific patient groups?  [Once again, I think, these questions (and the fact that they have gone virtually unaddressed in the research literature for decades), underscore the inadequacy of research that so often leaves the problem of heterogeneity (in symptoms, course, and outcomes) unaddressed. ]

Meltzer, a prominent pharmacology researcher and drug-developer whose research focuses on non-dopaminergic mechanisms of antipsychotic action, takes the journal forum as an opportunity to attack R and K’s putative over-emphasis on dopamine.  While this critique is interesting enough–Meltzer and colleagues’ work on the antipsychotic effects of selective 5-HT2A (serotonin 2A) inverse agonists, for instance, does suggest that the ‘story’ of real and potential AP efficacy is much more complicated than even the most updated version of Kapur’s ‘dopamine hypothesis’ (Version III)–it in no way addresses the potential relevance of research into extended dosing (whether we are dealing with dopamine antagonists, serotonin 2A inverse agonists, mGluR2/3 agonists, etc.) nor Goff’s well-taken point that regardless of the mechanisms responsible for various neurotoxic effects (mechanisms that remain largely poorly understood), any strategy that has the potential to ameliorate such effects while maintaining efficacy is worth investigating.

Shitij Kapur

When weighing the risks and benefits of antipsychotic drugs, is it always a question of continuing or discontinuing maintenance treatment?  Or are there other alternatives?  In their provocative recent review and commentary, Remington and Kapur suggest a particularly appealing third option: so-called extended dosing (taking a standard antipsychotic dose at intervals of 48-72 hours rather than daily or b.i.d.).  What’s the evidence behind this suggestion?

First and foremost, the authors suggest, studies regarding both oral and depot treatment demonstrate that continuously high levels of D2 occupancy are not necessary to retain antipsychotic response (that is, studies that have looked at occupancy levels over the course of day (in the case of oral treatments) or weeks (in depot administrations) have demonstrated significant variability).  If this is the case even in treatment as usual (24/7 or depot dosing), however, might it not be possible to take antipsychotics less frequently? Might such extended dosing even prevent dopaminergic upregulation (putatively reducing AP efficacy) and AP-induced neurotoxicity (including tardive dyskinesia)?

Albeit tentatively, this is exactly what R and K are suggesting.  First, two studies (one already published, one in press) demonstrated no increases in symptomatology and preliminary evidence of increases in subjective well-being in chronic patients.

Equally important, R and K present research suggesting that maintenance treatment may actually prevent or ameliorate the long-term reductions in antipsychotic efficacy often seen in chronic maintenance treatment as well as iatrogenic (drug-induced) neurotoxicity.  Using animal models, R, K and colleagues, for instance, have shown that rat models treated transiently show less ‘parkinsonian’ behaviors while chronically (but not transiently) treated rats show dopamine supersensitivity (higher than expected sensitivity to dopamine agonists) upon discontinuation. Further conditioned avoidance response (CAR)—a putative indicator of AP efficacy in rats—gradually decreases with maintenance treatment but is maintained under extended dosing.  Finally transient (but not chronic) dosing increases striatal and limbic homovanilic acid and c-fos MRNA in the caudate-putamen (putative efficacy markers also found in acute/single-dose treatment). This preclinical (animal research based) evidence meshes well with findings in clinical samples that suggest a gradual reduction in AP efficacy over time (as demonstrated by the relative efficacy of low-doses early on and much higher doses in chronic patients), as well as well as dopamine supersensitivity manifest in withdrawal psychosis (ala Chouinard et al.) and withdrawal dyskinesias (parkinsonian motor symptoms that commence as soon as APs are discontinued).