Julie Holland, M.D.
The purpose of this chapter is to familiarize the
reader with schizophrenia, and what is currently known about its symptoms,
their chemical basis, and their management. Also included in this
chapter are multiple reports from schizophrenics who have used MDMA.
I am presenting this anecdotal evidence to support the idea that MDMA may
help some schizophrenics to deal with the issues that arise when confronting
the presence of this disease. It is possible that the effects of
MDMA can temporarily reduce some of the acute symptoms of this illness,
or may help to equip schizophrenics with the power to fight their illness
chronically. It is not clear whether MDMA may or may not help a majority
of people with schizophrenia. What is clear, is that good clinical
research is necessary to explore the effects of single oral dose MDMA-assisted
psychotherapy in these patients. Whether the results of this proposed
research are miraculous or lackluster, they will nevertheless shed more
light on this disease and its pharmalogical management.
I have met all kinds of people
with schizophrenia. Since my college days, I have been fascinated
by the disease. I remember noticing people on the street, usually
homeless and acting bizarrely, that I thought might be ill. My main
reason for going to medical school and becoming a psychiatrist was to try
and help these particular patients.
One percent of the world's population has this diagnosis, or perhaps you should say suffers with this illness. Schizophrenia is a chronic mental illness characterized by a waxing and waning level of psychosis. Contrary to a widespread misunderstanding, schizophrenia does not mean multiple personalities. It is the split between thoughts and affect, between one's inner world and outer behavior that earned the disease its name. The hallmark features of schizophrenia are divided into two categories: positive symptoms and negative symptoms. Among the positive symptoms are auditory hallucinations (i.e. "hearing voices"), disorganized thoughts and speech, and paranoid delusions.
Imagine that you believe you are being monitored by the FBI, poisoned by your family, or perhaps that those around you have been replaced with imposters. It is common for you to have ideas of referenceó thinking that everything that is happening around you has something to do with you, that everything is a clue for you to interpret, or a secret code for you to translate. You are convinced that the purpose of a televised newscast or a song on the radio is specifically to send you a message. Other experiences that you may have are audible thoughts, or the belief that others can hear what you are thinking, as well as believing you can read people's minds and they yours. The voices in your head may keep up a running commentary of what is going on around you, or they may call you derogatory names, or may command you to do things.
Over the last fifty years, antipsychotic medications have been developed to help ease the symptoms of schizophrenia. Auditory hallucinations usually respond first to this treatment; the voices typically become quieter, although they do not always vanish. Speech then becomes more organized and less fragmented, perhaps because there is no longer competition from the voices while trying to speak. Paranoid delusions usually stick around a bit longer, as they are stubborn beliefs that take some time for people to abandon, but eventually they diminish in intensity as well.
After the positive symptoms have been adequately treated, the negative symptoms often remain. Although less disruptive, these can be quite debilitating, and are much more difficult to eradicate with typical antipsychotic medication. The deficit side of schizophrenia shows itself as amotivation, social isolation, talking less, and thinking less (known in psychiatry as poverty of speech and thought). Also present are some abberations in attention and concentration, usually referred to as cognitive deficits. Some schizophrenics have more negative symptoms than positive symptoms. Negative symptom-laden schizophrenics are at times reminiscent of people with autism. Emotionally withdrawn, they stay to themselves and may make rocking or other repeptitive motions, seeming quite disconnected from their environment. Also observed is affective blunting or flattening; if emotion is felt at all, it is not conveyed in their faces or voices.
Contrast this syndrome of paranoia, social withdrawal, decreased speech, motivation, and emotional expression with the syndrome seen during MDMA use: enhanced sociability, enthusiasm, euphoria, an increased desire to speak with and connect to others and a sense of openness and trust. It is easy to see why some people with schizophrenia have been drawn to MDMA use, and why they, and I, am eager for scientific research to move forward in this area. Because MDMA targets the very components of behavior that are affected in schizophrenia, and because MDMA enhances the function of the two brain chemicals that are implicated in the disease, these are two compelling reasons to explore the connection between this medication and this illness. It is quite possible that we may learn more about the biological basis of schizophrenia , its symptoms and its treatment, by learning more about MDMA.
The Dopamine Theory of Schizophrenia
In the early phases of schizophrenia
research, the dopamine theory dominated the scientific literature.
This hypothesis stated that the disease reflected a state in the brain
where there was too much dopamine, or an overactivity of the transmission
of dopamine (Meltzer, 1976). To support this, it was pointed out
that the most effective antipsychotics were those which blocked dopamine
receptors the most potently (Creese, 1976; Seeman, 1976). This receptor
blockade is known as dopamine antagonism. For many years, it was
felt that schizophrenia simply reflected a state of too much dopamine,
and its effective treatment was to antagonize the dopamine transmission.
More recent theories about dopamine and schizophrenia posit that there
may be an imbalance of dopaminergic activity, with the positive symptoms
(hallucinations and delusions) reflecting a "hyperdopaminergic" state in
certain parts of the brain (the subcortical regions) and negative symptoms
reflecting a "hypodopaminergic" state in the cortical, or prefrontal, region
(Deutch, 1992; Knable, 1997; Dworkin, 1992).
Another theory is that the negative symptoms may reflect actual structural changes in the brain (neuropathology) (Crow, 1980). Supporting this theory is the observation that people with frontal lobe injuries, for example those who have undergone frontal lobotomies or strokes, tend to have problems with initiating behaviors, showing emotion, and interacting appropriately with others (Neylan,1999). Interestingly, some stroke patients have been given amphetamine in order to enhance their motivation and hasten their recovery (Goldstein, 1999). Also seen in schizophrenia is a decreased rate of blood flow to the front part of the brain (Gur, 1989), while MDMA has been shown to enhance blood flow to some of the same areas often mentioned as abnormal in schizophrenics. In healthy normal volunteers given a single oral dose of MDMA (1.7 mg/kg), blood flow was increased bilaterally in the ventromedial prefrontal cortex, the ventral anterior cingulate, the inferior temporal lobe, the medial occipital lobe and in the entire cerebellum (Gamma,2000).
Clinical Studies: Giving Dopamine Agonists to Schizophrenics
What has become clear over time is
that while the classical antipsychotics which block dopamine receptors
can quiet the voices, organize the speech, and diminish the paranoia, they
do not adequately treat the deficit state or negative symptoms which remain.
Some researchers have stated that despite over twenty years of negative
symptom research, there is still no proven pharmacologic treatment for
primary negative symptoms (Carpenter, 1995). And so continues the
search for medications to ameliorate the negative symptoms. Some
medications which have been tried are dopamine agonists (enhancers) such
as amphetamine. Amphetamine has been used in psychiatry as early
as 1936 (Meyerson, 1936). It is widely accepted that chronic use
of high dose amphetamine, sometimes called a psycho-stimulant, can yield
a paranoid psychosis in non-psychiatric patients (Angrist, 1994); at one
time, this was part of the basis of the dopamine theory of schizophrenia
(Snyder, 1973; Ellison, 1994). Amphetamine, and other psychostimulants
such as ritalin and ephedrine, have been used in schizophrenia research
as "probes," or provocative tests. (see Lieberman, 1987 for a review)
The idea behind provocative tests is to give a drug which causes an effect,
any measureable effect at all in the schizophrenic population. Knowing
how the probe works chemically and observing its effect on the research
patients yields important information about the pharmacologic basis of
the symptoms and their treatment.
One theory of negative symptoms involves a failure of dopamine activation to the prefrontal cortex (an area of the brain felt to be involved in executive decision making) to explain some of the cognitive deficits seen in this syndrome (Dworkin, 1992). Therefore, it is felt that in smaller doses, psychostimulants such as the dopamine agonist amphetamine might be helpful in treating the deficit state of schizophrenia. There have been some studies showing that amphetamine can worsen a psychotic episode in schizophrenics (Guttman and Sargant, 1937; Angrist, 1980; Van Kammen, 1982). However, there were several other studies of schizophrenics which mentioned some decrease in negative symptoms with the administration of amphetmine (Angrist, 1982; Cesarec, 1985; Goldberg, 1991;Matthew , 1989; Van Kammen, 1988).
One study using schizotypal personality disordered patients, who tend to show similar affective flattening and cognitive deficits as schizophrenics, demonstrated amphetamine-associated improvement on a card sorting test typically affected in schizophrenia (Siegel,1996). Most amphetamine studies in negative-symptom laden schizophrenics qualify the statistically significant results seen as partial, but not complete. Although the results of these studies were not robust, one paper does caution that "amphetamine may modestly improve negative symptoms in those schizohprenics in whom this symptomatology is more severe." (Sanfilipo, 1996)
In reviewing the psychostimulant studies, a few trends are apparent: patients are less likely to become psychotic if the drugs are given orally, instead of intravenously, and if the patient is not acutely psychotic, but rather is showing residual, attenuated positive symptoms of schizophrenia. Methylphenidate (Ritalin) is reportedly more likely to bring on a psychotic episode than is amphetamine (Lieberman, 1987).
Important in the consideration to use MDMA in the treatment or study of schizophrenia is the following fact: the level of activity of the serotonergic system affects the response seen with amphetamine challenges. In animals, the results of a variety of tests in which serotonin was depleted or cells were lesioned showed a more robust repsonse to amphetamine challenges. Likewise, when serotonin availability was enhanced, there was an attenuation in amphetamine-elicited activation (Gerson, 1980). In schizophrenic subjects, when a serotonin precursor, 5-hydroxytryptophan, was given in conjunction with amphetamine, it prevented the induction of acute psychotic symptoms sometimes seen with amphetamine challenges (Irwin, 1987). Because MDMA acutely raises levels of serotonin and dopamine in the brain, this may prevent an increase in psychotic symptoms in schizohrenics.
Serotonin and Schizophrenia
Support for the involvement of
the serotonergic system in schizophrenia has been gathering in the literature
since it was first observed that lysergic acid diethylamide (LSD) caused
a syndrome evocative of schizophrenia in normal controls, and that the
structure of LSD shared similarities with serotonin (Gaddum, 1954).
Although the dopamine hypothesis dominated the literature for the next
three decades, further evidence to re-assert serotonergic abnormalities
in schizophrenics came as clozapine, the first antipsychotic in forty years
to demonstrate clinical superiority to chlorpromazine (Thorazine, a dopamine
antagonist), was found to have potent serotonin receptor antagonism (Meltzer,
Because the serotonergic system is functionally interactive (Kelland, 1990) and anatomically closely connected (Tork, 1991) with the dopaminergic system, there is good reason to view these two neurotransmitter systems in tandem, as opposed to each in isolation. The serotonin system inhibits dopaminergic function at both its origin in the midbrain and its termination in the forebrain (Kapur, 1996). Thus, it may be desirable to augment the dopamine antagonist treatment that is seen in classical antipsychotics with a serotonin agonist. Serotonin modulation may be beneficial in reducing the negative symptoms of schizophrenia (Leysen, 1993). It should be noted, however, that many of the newer antipsychotics are serotonin antgonists. This is a complex area of study. There are many different receptor subtypes of both serotonin and dopamine, and there are likely multiple modes of interaction between these two systems (Kapur, 1996). Also confounding, are the long term changes that take place in the brain when given chronic doses of serotonin and dopamine antagonists (e.g., antipsychotics) versus immediate effects seen with acute agonists of these same neurotransmitter systems, as is seen with MDMA.
The co-existing presence of illnesses known to respond to serotonin reuptake inhibitors (SSRIs like Prozac) lends support to the idea that serotonin is involved in the pathophysiology of schizophrenia. The prevalence of depression in schizophrenics is quite high and is seen throughout the course of the disease. Approximately 25% of schizophrenics experience depression following an acute psychotic episode ("post psychotic depression") and as many as 60% suffer a major depressive episode during the course of their illness (Bartels, 1988). One study found the incidence of depression to be twenty-two percent (22%) at baseline, and 26% over a five year follow up period (Koreen, 1993). The suicide rate for schizophrenics, ten to thirteen percent, is ten times the national average (1%) and is the leading cause of premature death in schizophrenia (Caldwell, 1990). A general population study showed that people with schizophrenia have the highest relative risk for attempted suicide, with a risk ratio of 23:1 (Dyck, 1988). Mann (1987) notes that a low level of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) measured in the cerebrospinal fluid (CSF) correlates with suicidal behavior in depression and in schizophrenia. One CSF 5-HIAA study noted low levels in schizophrenic patients, with a further reduction seen in those schizophrenics who had attempted suicide (Cooper, 1992). Clozapine treatment of neuroleptic resistant patients resulted in markedly less suicidality, and was accompanied by improvements in depression and hopelessness (Meltzer, 1995).
Schizophrenia and obsessive compulsive disorder show a high co-morbidity, perhaps reflecting the involvement of the serotonergic system in both of these psychiatric diseases. One study listed the occurrence of significant obsessive compulsive symptoms in schizophrenics as twenty five percent (Berman, 1995). Schizophrenia and Autism,too, share similar features (withdrawn behavior, self stimulation stereotypies, inappropriate or flattened affecct, poor eye contact). Some of these features of autism have been shown to respond to treatment with fenfluramine (Geller et al., 1982; Ritvo et al., 1983), a halogenated amphetamine with serotonin-agonist actions in behavioral models and serotonin-depleting actions in biochemical models (Clineschmidt, 1978) similar to MDMA.
Altered Markers of 5-HT function
Studies of platelet serotonin levels and receptor sites have further implicated the role of serotonin in schizophrenia. Increased levels of serotonin measured in platelets of schizophrenic and depressed research subjects were found to correlate with presence of psychotic symptoms. (Muck-Seler, 1991). Increased number of platelet serotonin binding sites were measured in drug-free schizophrenics (Pandey, 1993). Cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been shown to be reduced in schizophrenics in a number of studies (Potkin, 1983).
Several postmortem studies have demonstrated altered serotonin uptake site binding in schizophrenic brains (Joyce, 1993). This is the receptor site where SSRIs bind, and also where MDMA binds. The prefrontal cortex, frequently implicated in the neuropathology of schizophrenia, was shown to have selective abnormalities of serotonergic receptors in a post mortem study of schizophrenic patients. (Laruelle 1993) The findings of decreased binding sites in the frontal cortex and increased binding sites in the striatum lend support for the hypothesis that in schizophrenia there is an imbalance, cortical relative to subcortical, of serotonergic transmission, with the prefrontal cortex having a low or hyposerotonergic state, correlating with negative symptoms, and the subcortical structures exhibiting a high or a hyperserotonergic state, correlating with psychotic symptoms. (Breier, 1995)
Clinical Studies: Giving Serotonin Agonists to Schizophrenics
Several studies have used serotonin
reuptake inhibitors, particularly fluoxetine (Prozac), as an adjunctive
treatment in medicated schizophrenics. Fluoxetine has been shown
to significantly improve negative symptoms without worsening extra-pyramidal
side effects, although blood levels of neuroleptics were significantly
elevated. (Goff, 1995; Spina, 1994); fluvoxamine (Luvox) has also been
shown to ameliorate negative symptoms. (Silver, 1992). In a recent
study comparing fluvoxamine with maprotiline (a non-serotonergic antidepressant)
in medicated schizophrenics, those given fluvoxamine showed significant
improvement in motor retardation, emotional withdrawal, and affective blunting
as compared with the group given maprotiline (Silver, 1998). This
effectively factors out the possibility that it is merely an antidepressant
effect, and suggests that it is the serotonergic effect specifically, which
may be responsible for the improvement seen in negative symptoms.
In one study in which medicated schizophrenics received fenfluramine, three out of eight subjects showed statistically significant within-subject improvement in negative symptoms, and three other patients showed significant improvement in positive symptoms (Stahl, 1985). Fenfluramine has properties similar to MDMA, and rats trained to discriminate fenfluramine and placebo, tended to equate it with MDMA 90% of the time (Schecter,1997). However, another study using chronic fenfluramine treatment showed that it worsened negative symptoms in schizophrenic patients. (Soper, 1990). An open (unblind) trial of sertraline (Zoloft) administered to patients stabilized on antipsychotics noted some amelioration of both positive and negative symptoms (Thakore, 1996), while a double blind study found no statistically significant improvement (Lee, 1998).
Studies utilizing the serotonin agonist meta-chlorophenylpiperazine (mCPP) as a challenge test (single dose) in schizophrenic patients have been performed in an effort to test the assumption of serotonergic involvement in schizophrenia. They have produced mixed results. In normal subjects, mCPP infusion leads to increased body temperature, anxiety, and release of growth hormone, cortisol, ACTH and prolactin.(Murphy, 1991 and 1986) In a 1993 Yale study of neuroleptic-free schizophrenics, mCPP caused a larger anxious response in patients than in controls. Furthermore, it was shown to exacerbate psychotic symptoms in the patient group (Krystal, 1991). Iqbal (1991) corroborated the finding of psychotogenesis in schizophrenics exposed to an mCPP challenge (.25 mg/kg, pO), but Kahn (1991) actually measured an improvement in the symptoms (as measured by the Brief Psychiatric Rating Scale, or BPRS) of those schizophrenics undergoing an mcpp challenge (.35 mg/kg, pO).
What can be understood from all of the above results? Clearly, there is no simple answer. What was once a theory of too much dopamine or serotonin is now a theory of imbalance: too much in some areas, not enough in others. A few theorists go one step further to match the levels of neurotransmitters with symptomatology. Positive symptoms represent an abundance of dopamine turnover and negative symptoms represent the opposite (Rao, 1994). Because some people with schizophrenia have more positive or negative symptoms, some do better with certain medications, and some respond to others. There are many researchers who think that schizophrenia is a syndrome, or a group of illnesses, and not simply one disease. This may mean that if you are doing research on large groups of subjects, that you may not be studying the same phenomenon. Many studies now try to focus on positive-symptom or negative-symptom-predominant populations.
About the only thing that can be generalized from all this data is this: decreasing available dopamine and serotonin in the synapse seem to improve positive symptoms, and it's possible, though not nearly as certain, that enhancing available serotonin and dopamine in the synapse may improve negative symptoms.
There is one more interesting
piece to the puzzle. Schizophrenics are known to have deficits in
the way they process the outside world. Typically, people get used
to a repeptitive stimulus (habituation) and would have less of a response
to second and third presentations of the same thing. Also, there
is a phenomenon known as sensory gating, which is demonstrated well by
a tehnique known as pre-pulse inhibition (PPI). If a smaller stimulus
is given before a larger one, say two tones of escalating volume, typically
someone would be less startled by the second, louder tone, having been
prepared by the first, quieter tone. In schizophrenia this is not
the case, and this is known as a deficit in sensory gating, or a disruption
in PPI. There are many medicines and drugs which make this deficit
worse, but there are few substances which have been shown to enhance the
inhibition of the first pulse. Nicotine is one drug which does enhance
pre-pulse inhibition, which may explain why so many schizophrenics smoke
Recently, Swiss researchers have discovered that MDMA has the capacity to enhance PPI (Vollenweider, 1999). This may be the most compelling reason to give single oral dose MDMA to people with schizophrenia. If MDMA can enhance pre-pulse inhibition in the general population, it is possible it can enhance PPI in schizophrenia. Any medicine we can give that will ameliorate any symptom or syndrome is worth studying, if for no reason than to help us learn what the pharmacological basis of that symptom is, so better medications can be created. In the past, schizophrenics have been given LSD, DMT, PCP, amphetamine, ritalin, and ketamine in order to observe what effect these medications had on their symptoms. (Stol,1947; Boszormenyi,1958;, Itil,1967; Angrist,1980 and 1982; Lieberman,1987; Malhotra,1997; Lahti,1995) Many of these drugs worsened their symptoms for a short time. The rationale in performing these studies was that any observable change in symptomatology yields valuable information about the illness.
Given what we know about MDMA, which is that it increases the availability of serotonin and dopamine in the synapse, that it strengthens pre-pulse inhibition in humans, and that it does seem to reliably enhance sociality and motivation, it does seem reasonable to ask the question: Could it help people with schizophrenia? Connecting to and communicating with others is severely impaired in negative-symptom schizophrenics; it is markedly enhanced when taking MDMA in the rest of the population. Attention, concentration, and insight are all compromised in schizophrenics, yet augmented in someone experiencing MDMA. In the same way that amphetamine and fenfluramine have been used to try to ameliorate negative symptoms, so should the ring-substituted amphetamine MDMA.
The following "testimonials" are from people who have been diagnosed with schizophrenia, and have found, on their own, some benefit from their MDMA use. These are excerpts taken directly from their e mails to me describing their experiences.
Robert was diagnosed as paranoid schizophrenic in his early twenties. He had auditory and visual hallucinations, ideas of reference and paranoid ideation, and was treated with olanzepine.
"I strongly believe MDMA has huge potential
for the treatment of schizophrenia..."
"another commonality is a sense of well-being, not just in a personal sense, but also in a communal sense, a kind of belonging which can maqnifest itself as more "connected" conversations with people, or perhaps just more talking for those of few words. For me, this was a key factor in breaking down my own cycle of desocialization. On MDMA, I found myself more able to talk with almost anyone about almost anything, and felt rather freed of most (formerly unrealized or at least unadmitted) neuroses/psychoses that normally plague me." "Just this visceral experience of sharing thoughts and feelings with people, even if only for a few hours, did have a lasting effect on my own self- view and world-view. In some sense, it gives me something of a role-model for what sort of personality I would like to achieve without the use of external chemicals, and also gives direct proof that there is a lot of psychological flexibility in my own mind."
John was diagnosed with schizohrenia in his late teens. History of being treated with clozapine, olanzepine. Currently has been "de-diagnosed" and no longer takes any antipsychotic medication. (may have been misdiagnosed, though he did have a history of referential ideation and paranoia, never heard voices.)
"I have used MDMA quite successfully in combating my psychosis....With the very first use MDMA completely changed my life....The paranoia that I was experiencing was temporarily halted and replaced with an immense sense of love, compassion, intimacy and closeness. Please note that MDMA only reduced my paranoia temporarily, the paranoia came back later. But the insight that I gained from these precious few hours of clarity proved to be invaluable.... For one, I had now learned how to truly love, as the schizophrenia had removed that ability from me. I became closer to my friends and family. ...Secondly, I became a much more open, outgoing, and positive person. Again, schizophrenia had lobotomized these critical qualities from me. ...Finally, MDMA instilled in me an unrelenting will to live. A will to keep pushing on through my road to recovery no mattter what obstacles presented themselves. ... Through the positive MDMA effects, carefully titrated antipsychotic drugs, and having a lot of people who cared about me, I slowly began to turn the tide on my disease. Over time, I gradually worked my way to the point where I could live outside a psychiatric treatment facility. In fact, it's been over two and a half years since I left the hospital. the way I see it is that I will never have to go back, ever."
James' first signs of schizophrenia began around age 14 or 15. He has a history of persistent auditory hallucinations, paranoia, delusions, ideas of reference, one suicide attempt,and a psychiatric hospitalization.
"I felt as is if my mental problems had washed away. All of my paranoia, all of my reservations about people, all of the pent up anger and frustration, the bitterness towards my family, all of it had been flushed out with a single dose. I felt like a real person. I remember reflecting on my life in disgust at how I behave on a day to day basis, I wanted to initiate change, to make myself more like I was when I was on E, because I thought it was beautiful, and right. when I came down I wasn't disappointed that it was over, and I didn't crave more, but I did remember the changes I wanted to make." "My whole outlook on life changed that night." "It has given me freedom from a disease that has plagued me for years, and a bit of that freedom continues on even after the drug wears off." "I do not think this is a cure for anything, only a new perspective, that should be used wisely."
I also had an interesting telephone
call with a young man with schizophrenia whose symptoms were much more
severe than the other men I had spoken with. On a subsequent phone
call he was acutely paranoid, and he was eventually lost to follw up, but
he told me that when he took MDMA for the first time, he felt like he was
cured for a few hours, and he felt it was important that doctors and scientists
do reseach on why that had happened.
And I couldn't agree more.
Angrist B, Rotrosen J, Gershon S. Differential Effects of Amphetamine and Neuroleptics on Negative vs. Positive Symptoms in Schizophrenia. Psychopharmacology 1980; 72: 17-19
Angrist B, Peselow E, Rubinstein M, Corwin J, Rotrosen J. Partial Improvement in Negative Schizophrenic Symptoms After Amphetamine. Psychopharmacology 1982; 78: 128-130
Angrist B. Amphetamine Psychosis: Clinical Variations
of the Syndrome. in
Amphetamine And Its Analogs: Psychopharmacology, Toxicology, and Abuse. Cho A, Segal DS, eds. Academic Press, NY 1994
Bartels SJ, Drake RE: Depression in schizophrenia: current guidelines to treatment. Psychiatric Quarterlies 1989; 60:337-57
Berman I, Kalinowski A, Berman SM, Lengua J, Green AI: Obsessive and compulsive symptoms in chronic schizophrenia. Compr Psychiatry 1995; 36:6-10
Boszormenyi Z, Szara SI. Dimethyltryptamine experiments
psychotics. J Ment Sci 1958;104:445-53
Breier A: Serotonin, schizophrenia and antipsychotic drug action. Schizophrenia Research 1995; 14:187-202
Caldwell CB, Gottesman II: Schizophrenics kill themselves too: a review of the risk factors for suicide. Schizophrenia Bulletin 1990; 16:571-589
Canton G, Verriele L, Colpaert FC: Binding of typical and atypical antipsychotics to 5HT1c and 5HT2 sites: clozapine potently interacts with 5HT1c sites. Eur J Pharmacology 1990; 191:93-96
Carpenter WT Jr, Conley RR, Buchanon RW, Breier A, Tamminga CA: Patient response and resource management: another view ofclozapine treatment of schizophrenia. American Journal of Psychiatry 1995; 152: 827-832
Cesarec Z and Nyman AK. Differential Response to Amphetamine in Schizophrenia. Acta Psychiatrica Scandinavia 1985; 71: 523-538
Clineschmidt BV, Zacchei AG, Totaro JA, Pflueger AB, McGuffin JC,Wishousky TI. Fenfluramine and Brain Serotonin. Annals of the New York Academy of Science 1978; 305:222-241
Cooper SJ, Kelly CB, King DJ. 5-Hydroxyindoleacetic acid in cerebrospinal fluid and prediction of suicidal behavior in schizophrenia. Lancet 1992; 340:940-941
Creese I, Burt DR, Snyder SH. Dopamine receptor
binding predicts clinical and pharmacological potencies of antischizophrenic
drugs. Science 1976; 192:481-483
Crow TJ. Molecular Pathology of Schizophrenia: More Than One Disease Process? British Medical Journal 1980; 280:66-68
Deutch AY. The regulation of subcortical dopamine
systems by the prefrontal cortex: interactions of central dopamine
systems and the pathogenesis of schizophrenia. J Neural Transm Suppl 1992;36:61-89
Dworkin RH, Opler LA. Simple schizophrenia, negative symptoms, and prefrontal hypodopaminergia Am J Psychiatry 1992 Sep;149(9):1284-5
Dyck RJ, Bland RC, Newman SC, Orn H: Suicide attempts and psychiatric disorders in Edmonton. Acta Psychiatr Scand Suppl 1988;338:64-71
Ellison G. Stimulant-induced Psychosis, the Dopamine Theory of Schizophrenia, and the Habenula. Brain Research Reviews 1994; 19(2):223-239
Fuller RW, Wong DT: Serotonin uptake and serotonin uptake inhibition. Annals of New York Academy of Sciences 1990; 600:68-78
Gaddum J, Hameed K: Drugs which antagonize 5-hydroxytryptamine. Br J Pharmacology 1954; 9:240-248
Gamma A, Buck A, Berthold T, Liechti ME, Vollenweider
3,4-methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H2 15O]-PET in healthy humans.
Geller E, Ritvo ER,Freeman BJ, Yuwiler A. Preliminary Observations on the Effect of Fenfluramine on Blood Serotonin and Symptoms in Three Autistic Boys. New England Jurnal of Medicine 1982; 37:165-169
Gerson SC and Baldessarini RJ: Motor effects of serotonin in the central nervous system. Life Sciences 1980; 27: 1435-
Goff DC, Midha KK, Sarid-Segal O, Hubbard JW, AMico E: A placebo controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology Berl 1995; 117:417-423
Goldberg TE, Bigelow LB, Weinberger DR, Daniel DG, Kleinman JE. Cognitive and Behavioral Effects of Coadministration of Dextroamphetamine and Haloperidol in Schizophrenia. American Journal of Psychiatry 1991; 148: 78-84
Goldstein LB, Hulsebosch CE. Amphetamine-facilitated poststroke
Stroke 1999 Mar;30(3):696-8
Guttman E, Sargant W. Obserevations on Benzedrine. British Medical Journal 1937; 1:1013-1015
Gur RE, et al. Laterality and frontality of cerebral blood flow and metabolism in schizophrenia: relationship to symptom specificity. Psychiatry Res. 1989 Mar;27(3):325-34.
Iqbal N, Asins GM, Wetzler S, Kahn RS, Kay S, van Praag HM: The MCPP challenge test in schizophrenia: Hormonal and behavioral responses. Biological Psychiatry 1991; 30:770-7
Irwin MR, Marder SR, Fuentenbro F, Yuwiler A: L-5-Hydroxytryptophan attenuates positive psychotic symptoms induced by D-Amphetamine. Psychiatry Research 1987; 22: 283-289
Itil T, Keskiner A, Kiremitci N, Holden JM. Effect of phencyclidine in chronic schizophrenics. Can Psychiatr Assoc J. 1967 Apr;12(2):209-12
Joyce JN, Shane A, Lexow N, Winokur A, Casanovea MF, Kleinman JE: Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 1993; 8:315-336
Kahn RS, Siever LJ, Gabriel S, Amin F, Stern RG, Dumont K, Apter S, Davidson M: Serotonin function in schizophrenia: Effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects. Psychiatry Research 1992; 43:1-12
Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. American Journal of Psychiatry 1996; 153:466-476
Kelland MD, Freeman AS, Chiodo LA: Serotonergic afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. J Pharm Exp Ther 1990; 253:803-811
Knable MB, Weinberger DR Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol 1997;11(2):123-31
Koreen AR, Siris SG, Chakos M, Alvir J, Mayerhoff D, Lieberman J: Depression in first episode schizophrenia. Am J Psychiatry 1993; 150:1643-1648
Krystal JH, Seibyl JP, Price LP, Woods SW, Heninger GR, Charney DS: MCPP effects in schizophrenic patients before and after typical and atypical neuroleptic treatment. Schizophrenia Research 1991; 4:350-359
Krystal JH, Seibyl JP, Price LH, Woods SW, Heninger GR, Aghajanian GK, Charney DS: m-Chlorophenylpiperizine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia. Arch Gen Psychiatry 1993; 50:624-635
Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995 Aug;13(1):9-19
Laruelle M, and Maloteaux JM: Regional distribution of serotonergic pre- and postsynaptic markers in human brain. Acta Psychiatrica Scandinavia 1989; 80:56-59
Laruelle M, Abi-Dargham A, Casanova MF, Toti R, Weinberger DR, Kleinman JE: Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study. Arch Gen Psychiatry 1993; 50:810-818
Lee MS, Kim YK, Lee SK, Suh KY: A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia. Journal of Clinical Psychopharmacology 1998; 18: 399-403
Leysen JE, Janssen PMF, Schotte A, Luyten WHML, Megens AAHP: Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 1993; 112:S40-S54
Lieberman JA, Kane JM, Alvir J: Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 1987; 91: 415-433
Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A,
Pickar D, Breier A. Ketamine-induced exacerbation of psychotic symptoms
and cognitive impairment in neuroleptic-free schizophrenics.
Neuropsychopharmacology. 1997 Sep;17(3):141-50
Mann JJ: Psychobiologic predictors of suicide. J Clin Psychiatry 1987; 48:39-43
Matthew RJ and Wilson WH. Changes in Cerebral Blood Flow and Mental State After Amphetamine Challange in Schizophrenic Patients. Neuropsychobiology 1989; 21: 117-123
Meltzer H, Matsubara S, Lee J: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin 2 pKi values. J Pharmacol Exp Ther 1989; 251:238-246
Meltzer HY, Okayli G: Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry 1995; 152:183-190
Meltzer HY, Stahl SM: The dopamine hypothesis of schizophrenia: A review. Schizophrenia Bulletin 1976; 2:19-76
Meyerson A. Effect of Benzedrine Sulfate on Mood and Fatigue in Normal and Neurotic Persons. Archives of Neurology and Psychiatry 1936; 816-822
Muck-Seler D, Jakovljevic M, Deanovic Z: Platelet serotonin in subtypes of schizophrenia and unipolar depression. Psychiatry Research 1991; 38:105-113
Murphy DL, Lesch KP, Aulakh CS, et al.: Serotonin-selective arylpiperizines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol. Rev. 1991; 43:527-552
Murphy DL, Mueller EA, Garrick NA, Aulakh CS: Use of serotonergic agents in the clinical assessment of central serotonin function. J of Clinical Psychiatry 1986; 47:9-15
Neal-Beliveau BS, Joyce JN, Lucki I: Serotonergic involvement in haloperidol induced catalepsy. J Pharmacol Exp Ther 1993; 265:207-217
Neylan TC. Frontal lobe function: Mr. Phineas Gage's
J Neuropsychiatry Clin Neurosci. 1999
Pandey SC, Sharma RP, Janicak PG, MArks RC, Davis JM, Pandey GN: Platelet serotonin 2 receptors in schizophrenia: effects of illness and neuroleptic treatment. Psychiatry Research 1993; 48:57-68
Potkin SG, Weinberger DR, Linnoila M et al.: Low CSF 5-hydroxyindoleacetic acid in schizophrenic patients with enlarged cerebral ventricles. Am J of Psychiatry 1983; 140:21-25
Rao ML, Moller HJ. Biochemical Findings of Negative Symptoms in Schizophrenia and Their Putative Relevance to Pharmacologic Treatment. Neuropsychobiology 1994; 30: 160-172.
Ritvo ER, Freeman BJ, Geller E, Yuwiler A. Effects of Fenfluramine on 14 Outpatients with the Syndrome of Autism. Journal of American Academy of Child Psychiatry 1983; 22:549-558
Sanfilipo M, Wolkin A, Angrist B, van Kammen DP, Duncan E, Wieland S, Cooper TB, Peselow ED, Rotrosen J. Amphetamine and Negative Symptoms of Schizophrenia. Psychopharmacology 1996; 123: 211-214
Schecter MD. Serotonergic Mediation of Fenfluramine Discriminative Stimuli in Fawn-Hooded Rats. Life Science 1997;60(6):PL83-90
Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261:717-719
Siegel BV Jr., Trestman RL, O'Flaithbhearthaigh S, Mitropolou V, Amin F, Kirrane R, Silverman J, Schmeidler J, Keefe RS, Siever LJ. D-amphetamine Challenge Effects on Wisconssin Card Sort Test. Performance in Schizotypal Personality Disorder. Schizophrenia Research 1996; 20(1-2):29-32
Silver H, Nassar A: Fluvoxamine improves negative symptoms in treated chronic schizophrenia. Pharmacopsychiatry 1992; 25:245
Silver H and Shmugliakov N. Augmentation with Fluvoxamine but not Maprotiline Improves Negative Symptoms in Treated Schizophrenia. Journal of Clinical Psychopharmacology 1998;18:208-211
Snyder SH: Amphetamine psychosis: A "model" schizophrenia mediated by catecholamines. American Journal of Psychiatry 1973; 130: 61-67
Soper HV, Elliot Jr. RO, Rejzer AA et al.: Effects of
fenfluramine on neuropsychological and communicative functioning in treatment
schizophrenic patients. J Clin Psychopharmacology 1990; 10:168-175
Spina E, DeDomenico P, Ruello C, Longobardo N, Gitto C, Ancione M, DiRosa AE, Caputi AP: Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizoprhenic patients. Int Clin Psychopharmacology 1994; 9:281-285
Stahl SM, Uhr SB, Berger PA. Pilot Study on the Effects of Fenfluramine on Negative Symptoms in Twelve Schizophrenic Inpatients. Biological Psychiatry 1985;20:1098-1102
Stol W. Lysergaure-diathyl-amid, ein Phantastikum aus der Mutterkorngruppe. [LSD, a hallucinatory agent from the ergot group.] Schweitz. Arch. Neut. 1947;60
Suehiro M, Ravert HT, Dannals RF, Scheffel U, Wagner Jr. HN: Synthesis of a radiotracer for studying serotonin uptake sites with positron emission tomography: [11C]McN-5652-Z. J Lab. Comp. Radiopharm. 1992; 31:841-848
Suehiro M, Scheffel U, Dannals R, Ravert HT, Ricaurte GA, Wagner HN: A PET radiotracer for studying serotonin uptake sites: Carbon-11-McN-5652Z. The J of Nuclear Medicine 1993; 34:120-127
Szabo Z, Kao PF, Scheffel U, Suehiro M, Matthews WB, Ravert HT, Musachio JL, Marenco S, Kim SE, Ricaurte GA, et al: Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652. Synapse 1995; 20:37-43
Talairach J, Tournoux P: Co -planar Stereotaxic Atlas of the Human Brain 3-D Proportional System: An Approach to Cerebral Imaging. London, Thieme, 1988
Thakore JH, Berti C, Dinan TG: An open trial of adjunctive sertrline in the treatment of chronic schizophrenia. Acta Psychiatrica Scandinavica 1996; 94: 194-197
Tork I: Anatomy of the serotonergic system. Ann NY Acad Sci 1991; 600:9-34
Van Kammen DP and Boronow JJ. Dextro-Amphetamine Diminishes Negative Symptoms in Schizophrenia. International Clinical Psychopharmacology 1988; 3: 111-121
Vollenweider FX, et al. Opposite effects of 3,4-methylenedioxymethamphetamine(MDMA) on sensorimotor gating in rats versus healthy humans. Psychopharmacology (Berl). 1999 Apr;143(4):365-72.
Woods RP, Cherry SR, Mazziotta JC: Rapid automated algorithm
for aligning and reslicing PET images. J of Computer Assisted Tomography