Psychobiology Of Major Affective Disorders

Overview Of History –
Personal History And Review Of Research –
Current Research –
Faculty And Staff –
Contact Us –
Publications: Bibliography

Overview Of History

Dr. Joseph J. Schildkraut is Professor of Psychiatry at Harvard Medical
School and Founding Director of the Neuropsychopharmacology/Psychiatric
Chemistry Laboratory at the Massachusetts Mental Health Center (MMHC)
in Boston. Dr. Schildkraut received his A.B. summa cum laude from Harvard
College in 1955, where he was elected to Phi Beta Kappa in his junior
year, and his M.D. cum laude from Harvard Medical School in 1959. He received
his residency training in psychiatry at the Massachusetts Mental Health
Center from 1960-1963, where he began his research on depression and catecholamines;
and he furthered his research training in neuropsychopharmacology at the
National Institute of Mental Health in Bethesda, Maryland from 1963-1967.
In 1967 Dr. Schildkraut returned to the MMHC and joined the faculty of
Harvard Medical School as an assistant professor of psychiatry. He became
an associate professor of psychiatry in 1970 and a professor of psychiatry
in 1974.

Dr. Schildkraut’s seminal paper, The Catecholamine Hypothesis of
Affective Disorders, published in 1965, set the agenda for biological
research on depression for the next 25 years. This paper, which crystallized
a new way of thinking about mood disorders and pushed forward a paradigmatic
shift in the understanding of their pathophysiology and putative etiology
(Healy, D. The Antidepressant Era, Harvard University Press, 1997, pp.
155-161), is the most frequently cited of all articles ever published
in The American Journal of Psychiatry and one of the most cited papers
in all of psychiatry. At the time it was published, The Catecholamine
Hypothesis captured the imagination of the field, demonstrating how pharmacology,
by providing a bridge linking neurochemistry and clinical psychiatry,
could offer a rational approach to research in clinical neurosciences.
Moreover, on a broader scale, these ideas eventually reached the popular
culture and helped lessen the stigma of psychiatric illness, emerging
as the view that depressions are medical illnesses and that many mental
disorders are related to “chemical imbalances.”

This article was selected as a “Classic Article in Neuropsychiatry”
and reprinted in the Journal of Neuropsychiatry and Clinical
Neuroscience in 1995 (Fall), the first year that this Series was
published in the Journal.

David Healy,
in his book, The Psychopharmacologists III (Oxford University Press, 2000,
page xxxiv) wrote: “More than any other paper, Joe Schildkraut’s
Catecholamine Hypothesis defined the psychopharmacological era. One may
quibble with the details of the hypothesis, but the paper was foundational
– the 1960’s equivalent to Freud’s The Interpretation
of Dreams.” (See also Healy, 2000, pp. 111-134.)

Upon returning to the Massachusetts Mental Health Center in 1967, Dr.
Schildkraut founded the Neuropsychopharmacology Laboratory (which some
years later developed a subcomponent, the Psychiatric Chemistry Laboratory,
which functioned as a clinical laboratory under the aegis of the Department
of Pathology at the New England Deaconess Hospital). In the course of
his pathfinding studies of mood disorders conducted in the Neuropsychopharmacology/Psychiatric
Chemistry Laboratory, Dr. Schildkraut and his collaborators, fellows,
and medical students elucidated the role of catecholaminergic neurotransmitters
in the mechanisms of action of antidepressant drugs and showed that subtypes
of depressive disorders could be differentiated biochemically on the basis
of measures of catecholamine metabolism. This research
was supported in part by a grant from NIMH (RO1MH15413) that was continuously
funded for 25 years.

In a recent aspect of his research, Dr. Schildkraut and his colleague,
Dr. John J. Mooney, developed a reconceptualization of the process of
inactivation and metabolism of norepinephrine released into the synapse.
This led to a reformulation of the mechanisms of action of norepinephrine
reuptake inhibitor antidepressant drugs. On this basis, they developed
a proposal for a rapidly acting antidepressant. Working through the Harvard
Medical School Office of Technology Licensing and Industry-Sponsored Research,
Drs. Schildkraut and Mooney filed a patent application, Antidepressant
Effect of Norepinephrine Uptake 2 Inhibitors and Combined Medications
Including Them, on March 16, 2001, and this patent was approved on June
11, 2002. Negotiations with major pharmaceutical companies are currently
underway.

In addition, Dr. Schildkraut was involved in the development and progress
of Harvard’s Commonwealth Research Center (CRC) based at the Massachusetts
Mental Health Center. For many years, in its initial phase of development,
Dr. Schildkraut served as the Chair of the CRC Scientific Advisory Board,
and he subsequently served as senior mentor and collaborator with Alan
I. Green, M.D. and other members of the CRC in their program of research
on schizophrenia. During the course of Dr. Green’s research on the
CRC, Dr. Schildkraut’s laboratory became an integral component of
the Commonwealth Research Center.

For the past fifteen years, Dr. Schildkraut also has been exploring the
inter-relatedness of depression, spirituality and artistic creativity,
and his papers on this subject have appeared in leading peer-reviewed
professional journals. Moreover, he is editor of the book, Depression
and the Spiritual in Modern Art: Homage to Miró, published by John
Wiley & Sons, Ltd. in 1996. This book is based on an international
symposium that Dr. Schildkraut organized and chaired in 1993 that was
held in Barcelona at the Joan Miró Foundation at the time of their
centenary celebration of the birth of Joan Miró.

Former Editor-in-Chief of the Journal of Psychiatric Research, Dr. Schildkraut
is the author of over 200 scientific publications. His pioneering research
on the neurochemistry and neuropharmacology of depressive disorders has
been recognized with many awards and prizes including: the Anna Monika
Foundation Prize for Research in Endogenous Depressions in 1967, the first
year that this international prize was awarded; the Hofheimer Prize for
Research from the American Psychiatric Association in 1971; the William
C. Menninger Memorial Award from the American College of Physicians in
1978; a Lifetime Achievement Award from the Society of Biological Psychiatry
in 1996, presented at the Society’s 50th Annual Meeting to “seminal
founding scientists in the field;” and The Award for Research in
Mood Disorders from The American College of Psychiatrists in 1999.

Back To Top

Personal History And Review Of Research

I came to the Massachusetts Mental Health Center (MMHC) in 1960, planning
to become a psychoanalyst. However, during my first year of residency, the
antidepressant drugs, phenelzine (a monoamine oxidase inhibitor) and imipramine
were just being introduced at MMHC for the treatment of depressed patients.
When I became aware of the remarkable clinical effects of these antidepressants
compared to psychotherapy alone (which, with the exception of electroconvulsive
treatment, had been the standard and only treatment for depressed patients
up until that time) it became clear to me that I had to learn more about
the possible mechanisms of action of these clinically effective antidepressant
drugs.

It was my good fortune that Milton Greenblatt, the Assistant Superintendent
at MMHC, who was in the process of developing a small research unit for
the study and treatment of depressed patients, asked me if I would be
willing to become the “chief”(and as it turned out the only) resident of this research ward.
This was a wonderful opportunity that I could not refuse. The ongoing
research on this unit enabled me to conduct a study comparing the effects
of phenelzine and imipramine on the excretion of VMA (a major metabolite
of norepinephrine) in depressed patients. Since the conversion of norepinephrine
to VMA requires the enzyme monoamine oxidase, the aim of this study was
to determine whether, in clinical use, phenelzine (the monoamine oxidase
inhibitor) would, in fact, decrease the urinary output of VMA. In addition
to a placebo comparison group, this study also included a comparison group
of patients treated with imipramine, which is not a monoamine oxidase
inhibitor, and which was, therefore, not expected to produce a change
in VMA.

While there was no change in VMA output in patients treated with placebo,
as we had hypothesized, VMA was markedly reduced in patients treated with
phenelzine. We were very surprised, however, to find that treatment with
imipramine also produced a decrease in VMA (Schildkraut et al., “Excretion
of 3-methoxy-4-hydroxymandelic Acid (VMA) in Depressed Patients Treated
with Antidepressant Drugs,” Journal of Psychiatric Research, 1964).
The unexpected finding that treatment with imipramine decreased VMA led
to my thoroughly reviewing the rather modest basic pharmacological literature
pertaining to these antidepressants (at that time) and, thus, developing
an “expertise” in the emerging field of neuropsychopharmacology.
As a result, Seymour Kety invited me to become an associate in his Laboratory
of Clinical Science at the National Institute of Mental Health (NIMH)
upon completion of my residency in 1963. I went on to NIMH to spend the
next four years of my career (1963-67) extending my clinical research
in neuropsychopharmacology on Jack Durell’s unit, and beginning
my career in basic neuropharmacology, collaborating with Saul Schanberg
in Irv Kopin’s neuropharmacology laboratory.

The first study I performed at the NIMH was an attempt to replicate our
research on the effects of imipramine on VMA excretion and to extend it
to other aspects of norepinephrine metabolism. In that first study, we
confirmed that imipramine decreased VMA excretion. Moreover, we also observed
that normetanephrine (the O-methylated metabolite of norepinephrine),
which was thought to derive from norepinephrine that was released into
the synapse, was increased and that increase seemed to be related to the
clinical antidepressant effects of imipramine (Schildkraut et al., “Catecholamine
Metabolism in Affective Disorders: I. Normetanephrine and VMA Excretion
in Depressed Patients Treated with Imipramine,” Journal of Psychiatric
Research, 1965). This was of considerable interest, since Julie Axelrod
had previously discovered that the major mechanism for inactivating norepinephrine
released into the synapse was by reuptake of that norepinephrine into
the presynaptic neuron of origin, and that imipramine blocked this reuptake.

Early on in my career at NIMH I became aware that there was very little
cross-talk between the clinical psychiatrists and the basic neuropharmacologists,
and it appeared to me that there was a need for review of the psychiatric
implications emerging from ongoing neuropharmacological studies of norepinephrine
and other catecholamines. Thus, I came to write a paper entitled, “The
Catecholamine Hypothesis of Affective Disorders: A Review of Supporting
Evidence” that was published in The American Journal of Psychiatry
in 1965, and which came to be the most frequently cited paper ever published
in The American Journal of Psychiatry.

Following up on Julie Axelrod’s work, my colleagues and I (in Irv
Kopin’s laboratory) found that, in animals, a variety of tricyclic
antidepressant drugs blocked the reuptake of norepinephrine into the presynaptic
neuron of origin, while simultaneously increasing brain levels of normetanephrine.
Moreover, we found that acute administration of these drugs appeared to
slow the release of norepinephrine from the brain (Schanberg et al., “The
Effects of Psychoactive Drugs on Norepinephrine-H3 Metabolism in Brain,”
Biochemical Pharmacology, 1967; Schildkraut et al., “Norepinephrine
Metabolism and Drugs Used in the Affective Disorders: A Possible Mechanism
of Action,” The American Journal of Psychiatry, 1967. In further
studies (Schanberg et al., “Metabolism of Normetanephrine-H3 in
Rat Brain,” Biochemical Pharmacology, 1968), we went on to show
that the major metabolite of normetanephrine in rat brain was the sulfate
conjugate of 3-methoxy-4-hydroxyphelynglycol (MHPG).

In 1967, I returned to MMHC and established a neuropsychopharmacology
laboratory. One of the goals of this laboratory was to develop a program
of research to explore the mechanisms of action of antidepressant drugs.
Initially, I planned to study the neuropsychopharmacological effects of
long-term administration of tricyclic antidepressant drugs, since chronic
administration is required to achieve clinical antidepressant effects,
and virtually all of the previous studies of the neuropharmacology of
these antidepressants involved acute administration. Thus, after all laboratory
assays had been standardized, my first major study was to compare the
effects of acute and chronic (three weeks) administration of imipramine
on the turnover and metabolism of norepinephrine in rat brain.

In these studies, we confirmed the earlier findings that the release
of norepinephrine from rat brain was decreased after a single administration
of imipramine. During long-term administration (three weeks) of imipramine,
however, the release of norepinephrine from brain gradually increased
(“Schildkraut et al., “Norepinephrine Turnover and Metabolism
in Rat Brain After Long-Term Administration of Imipramine,” Science,
1970). In that paper, we suggested that these findings may help to explain
why antidepressant effects are observed clinically only after long-term
treatment with imipramine; and in further studies, we went on to confirm
and extend these findings (Schildkraut et al., “Changes in Norepinephrine
Turnover in Rat Brain During Chronic Administration of Imipramine and
Protriptyline: A Possible Explanation for the Delay in Onset of Clinical
Antidepressant Effects,” The American Journal of Psychiatry, 1971).

Another goal of our research was to determine whether various subtypes
of depressive disorders showed differences in the output and metabolism
of norepinephrine. Since our earlier studies had shown that MHPG was the
major metabolite of norepinephrine in rat brain, in a preliminary study
we compared levels of urinary MHPG in patients with manic-depressive depressions
(i.e., bipolar disorders) and patients with unipolar chronic characterological
depressions. In this preliminary study we observed that urinary MHPG levels
were significantly lower (p<.05) in patients with manic-depressive depressions than in patients with chronic characterological depressions (Schildkraut et al., “MHPG Excretion and Clinical Classification in Depressive Disorders,” Lancet, 1973). The findings of this preliminary study led us to develop a program of research that we called “Toward a Biochemical Classification of Depressive Disorders”; the findings from this research on the biochemical pathophysiology of depressive disorders were reported in a series of ten papers published from 1978 to 1989.

In the first of these studies (Schildkraut et al., “Toward a Biochemical
Classification of Depressive Disorders I: Differences in Urinary MHPG
and Other Catecholamine Metabolites in Clinically Defined Subtypes of
Depressions,” Archives of General Psychiatry, 1978a), we examined
the differences in levels of urinary MHPG and other catecholamine metabolites
in 63 patients with various clinically defined subtypes of depressive
disorders: manic-depressive depressions, schizo-affective depressions
(see paper Schildkraut et al., Archives of General Psychiatry, 1978a cited
above for definition of schizo-affective depressions used in this study),
unipolar endogenous depressions, unipolar nonendogenous depressions, and
schizophrenia-related depressions. Urinary MHPG
levels were significantly lower in patients with bipolar manic-depressive
and schizo-affective depressions than in patients with unipolar non-endogenous
depressions. In patients with unipolar endogenous depressions, we observed
a wide range of MHPG levels with some patients showing levels comparable
to those seen in patients with bipolar manic-depressive depressions, and
others showing urinary MHPG levels that were higher than those seen in
patients with unipolar nonendogenous depressions. (It is possible that
some of those patients with low levels of urinary MHPG may, in fact, have
been patients with bipolar disorders who had not yet experienced their
first episode of mania.)

In addition to levels of urinary MHPG, we also measured urinary norepinephrine,
epinephrine, and various other metabolites of these catecholamines, including
VMA, normetanephrine, and metanephrine. Further biochemical discrimination
among these clinically defined subtypes of depressive disorders was obtained
using an empirically derived multivariate discrimination equation based
on these biochemical data (Schildkraut et al., “Toward A Biochemical
Classification of Depressive Disorders II: Application of Multivariate
Discriminant Function Analysis to Data on Urinary Catecholamines and Metabolites,”
Archives of General Psychiatry, 1978). Multivariate discriminant function
analysis was applied to the data on catecholamines and metabolites obtained
from an initial series of patients with bipolar manic-depressive depressions
and unipolar nonendogenous (chronic characterological) depressions. The
terms available for computer entry into this equation included: norepinephrine
(NE), normetanephrine (NMN), epinephrine (E), metanephrine (MN), vanillylmandelic
acid (VMA), 3-methoxy-4-hydroxyphenglycol (MHPG), and various sums and
ratios of these terms.

Based on these terms, a discrimination equation was developed in a stepwise
procedure where the variable selected by the computer for entry into the
equation at each step was the one with the largest contribution to discrimination
(when the information shared with items already entered was partialed
out). Thus, this equation was determined by an analytic procedure that
was not influenced by the investigators.

The equation for what we term the, “Depression-type” (D-type)
score was of the form:
D-type score = C1 (MHPG) – C2 (VMA) + C3 (NE) – C4 (NMN + MN)/VMA + C0
These four terms were selected from the terms available to the computer
because each made a statistically significant (p<.01) contribution to the discrimination between bipolar manic-depressive depressions and unipolar nonendogenous (chronic characterological) depressions. No other terms added significantly to the discrimination obtained from these four terms, and the overall accuracy of discrimination was highly significant. In developing the metric for this equation, a value of 0 was assigned to bipolar manic-depressive depressions and the value 1 was assigned to unipolar nonendogenous depressions. Therefore, in the application of this equation, D-type scores less than 0.5 are associated with bipolar manic-depressive depressions and D-type scores greater than 0.5 are associated with unipolar nonendogenous depressions.

This equation was then applied to data on urinary catecholamines and
metabolites in an independent series of 33 depressed patients who were
studied after the derivation of this equation, and whose biochemical data,
therefore, had not been used to derive the parameters of the equation.
In this validation sample all of the patients with clinical diagnoses
of bipolar manic-depressive or schizo-affective depressions had D-type
scores below 0.5. In contrast, all of the patients with diagnoses of unipolar
nonendogenous depressions, as well as all patients with schizophrenia-related
and unclassifiable depressions had D-type scores above 0.5.

The 9 patients with unipolar endogenous depressions had a wide range
of D-type scores, with several below 0.5 and, clearly, in the range observed
in bipolar manic-depressive or schizo-affective depressions. Thus, D-type
scores below 0.5 may conceivably help to identify from within the overall
group of unipolar endogenous depressions, those patients with a biochemical
similarity or predisposition to bipolar manic-depressive (or schizo-affective)
disorders, even though the patient may not have a history of prior overt
episodes of hypomania or mania.

The fourth term of the equation, which is the ratio (NMN + MN)/VMA, may
reflect differences in monamine oxidase (MAO) activity between the subtypes
of depressive disorders. Since NMN and MN can be converted to VMA (or
MHPG) by deamination, this ratio may be inversely related to MAO activity.
On the basis of measurements of platelet MAO activity, some investigators
have suggested that MAO activity may be reduced in patients with bipolar
manic-depressive disorders, and increased in patients with other types
of depressive disorders. This would be consistent with the fact that the
ratio (NMN + MN)/VMA appears in the equation with a negative coefficient.

D-type scores and platelet MAO activity data were obtained from patients
concurrently. Platelet MAO activity was significantly lower in depressed
patients with D-type scores less than 0.5 than in depressed patients with
D-type scores greater than 0.5. These findings, showing that patients
with low versus high D-type scores have a significant difference in an
independent biochemical measure, further suggests that D-type scores may
be discriminating among biologically meaningful subtypes of depressive
disorders. Moreover, these findings are consistent with the possibility
that the fourth term of the discrimination equation for D-type scores
may reflect MAO activity.

This D-type equation may provide an even more precise discrimination
among biologically meaningful subtypes of depressive disorders than does
the level of urinary MHPG alone. Thus, it is intriguing to speculate that
the discrimination equation, by including the contribution of various
urinary catecholamine metabolites of peripheral origin may be correcting
for the fraction of urinary MHPG that derives from the periphery, rather
than the brain.

In a further study (Schatzberg et al., “Toward a Biochemical Classification
of Depressive Disorders X: Urinary Catecholamines, Their Metabolites,
and D-type Scores in Subgroups of Depressive Disorders,” Archives
of General Psychiatry, 1989), data on 24-hour urinary levels of catecholamines
and metabolites were determined in 114 depressed patients. For each patient,
a D-type score was calculated from the previously derived D-type equation.
Of all biochemical measures obtained, D-type scores provided the highest
sensitivity and specificity for separating bipolar manic-depressive/schizo-affective
depressed patients from all remaining patients.

Moreover, a further study (Mooney et al., “Urinary 3-Methoxy-4-hydroxyphenylglycol
and the Depression-Type Score as Predictors of Differential Responses
to Antidepressants,” 1991) examined pretreatment 24-hour urinary
MHPG levels and the D-type score as possible predictors of antidepressant
responses to either imipramine or alprazolam. In the case of imipramine,
the responders had significantly lower pretreatment urinary MHPG levels
(p=.002) and D-types scores (p<.001) than did nonresponders. In contrast, responders to the antidepressant effects of alprazolam had significantly higher pretreatment urinary MHPG levels (p<.05) and D-type scores (p=.001) than did nonresponders. For each antidepressant treatment, D-type scores appeared to provide a better separation of responders from nonresponders than did urinary MHPG levels. These findings show that D-type scores, which were initially derived to separate bipolar manic-depressive depressions from other subgroups of depressive disorders, also appear to predict differential responses to certain antidepressant drugs in patients with unipolar depressions. Thus, this observation extends the potential clinical utility of the D-type equation and enhances the heuristic value of this empirically derived equation as a theoretical model that may provide clues concerning the underlying biochemical pathophysiology of catecholaminergic neuronal systems in patients with depressive disorders.

On June 11, 2002, Drs. Schildkraut and Mooney were awarded a United States
patent (Patent No.: US 6,403,645 B2) entitled, Antidepressant Effect of
Norepinephrine Uptake 2 Inhibitors and Combined Medications Including
Them, concerning a rapidly acting antidepressant. This patent proposed
that normetanephrine or other inhibitors of the extraneuronal monoamine
transporter (uptake 2) in brain would speed up the clinical antidepressant
effects of norepinephrine reuptake inhibitor antidepressant drugs.

In recent years, collaborating with Dr. Alan I. Green, Dr. Schildkraut
and members of the Neuropsychopharmacology/Psychiatric Chemistry Laboratory
focused their research on the neuropsychopharmacology of clozapine (Green
et al., “Clozapine Response and Plasma Catecholamines and Their
Metabolites,” Psychiatry Research, 1993; Green and Schildkraut,
“Should Clozapine be a First Line Treatment for Schizophrenia?:
The Rationale for a Double-Blind Clinical Trial in First Episode Patients,”
Harvard Review of Psychiatry, 1995; Green et al.,
“Clozapine for Comorbid Substance Use Disorder and Schizophrenia:
Do Patients with Schizophrenia Have a Reward-Deficiency Syndrome that
Can Be Ameliorated by Clozapine?,” Harvard Review of Psychiatry,
1999).

Over the years, in another aspect of the research of the Neuropsychopharmacology/Psychiatric
Chemistry Laboratory, Dr. John J. Mooney has spearheaded a series of studies
concerning biochemical methodologies and basic neuropsychopharmacological
studies. This work includes Mooney et al., “An Improved Method for
the Homogenization of Human Platelets Using Colchicine and Nitrogen Decompression,”
Biochemical Medicine, 1981; Mooney et al, “Platelet Monoamine Oxidase
Activity in Psychiatric Disorders. The Application of a Technique for
the Isolation of Free Platelet Mitochondria from Relatively Small Blood
Samples,” Journal of Psychiatric Research, 1981; Mooney et al.,
“Sodium Inhibits Both Adenylate Cyclase and High-Affinity [3H]-p-aminoclonidine
Binding to Alpha-Adrenergic Receptors in Purified Human Platelet Membranes,”
Molecular Pharmacology, 1982; Mooney et al., “Enhanced Signal Transduction
by Adenylate Cyclase in Platelet Membranes of Patients Showing Antidepressant
Responses to Alprazolam: Preliminary Data,” Journal of Psychiatric
Research, 1985; “Mooney et al., “Rapid Antidepressant Response
to Alprazolam in Depressed Patients with High Catecholamine Output and
Heterologous Desensitization of Platelet Adenylate Cyclase,” Biological
Psychiatry, 1988; and Mooney et al., “Mooney et al., “Signal
Transduction by Platelet Adenylate Cyclase: Alterations in Depressed Patients
May Reflect Impairment in the Coordinated Integration of Cellular Signals
(Coincidence Detection),” Biological Psychiatry, 1998.

For the past fifteen to twenty years, Dr. Schildkraut also has been exploring
the inter-relatedness of depression, spirituality and artistic creativity,
and his papers on this subject have appeared in leading professional journals.
He is editor of the book, Depression and the Spiritual in Modern Art:
Homage to Miro, published by John Wiley & Sons, Ltd. in August, 1996.

These studies include: Schildkraut, “Miró and the Mystical
in Modern Art: Problems for Research in Metapsychiatry,” The American
Journal of Social Psychiatry, 1982; Schildkraut et al., “Mind and
Mood in Modern Art II: Depressive Disorders, Spirituality and Early Deaths
in the Abstract Expressionist Artists of the New York School,” The
American Journal of Psychiatry, 1994; and Schildkraut and Hirshfeld, “Mind
and Mood in Modern Art I: Miró and ‘Melancolie’,”
Creativity Research Journal, 1995. Moreover, in 1993, Dr. Schildkraut
organized and chaired a symposium on “Depression and the Spiritual
in Modern Art: Homage to Miró that was held at the Miró
Foundation in Barcelona. John Wiley & Sons, Ltd. published the proceedings
of this symposium in 1996 in a volume entitled, Depression and the Spiritual
in Modern Art: Homage to Miró. This book was edited by Joseph J. Schildkraut, M.D. and Aurora Otero, M.D. Dr. Schildkraut’s papers in
this symposium included “’Rain of Lyres Circuses of Melancholy:’
Homage to Miró” in collaboration with Alissa J. Hirshfeld
and “Depressive Disorders, Spirituality, and Early Deaths in the
Abstract Expressionist Artists of the New York School” in collaboration
with Alissa J. Hirshfeld and Jane M. Murphy.

Back To Top

Current Research

1. Promotion of patent and exploration of the development of inhibitors
   of the extraneuronal monoamine transporter (uptake 2)
2. Continued analyses of data on catecholamines and adenylate cyclase
   in study of depressed patients treated with desipramine
3. Exploration of the hypothesis that Rembrandt experience a period of
   depression at midlife (This study is being done in collaboration with
   Marjorie B. Cohn, Carl A. Weyerhaeuser, Curator of Prints at Harvard’s
   Fogg Art Museum, and Acting Director of Harvard University Art Museums.)

Back To Top

Faculty And Staff

Joseph J. Schildkraut, M.D.
Professor of Psychiatry Harvard Medical School and Senior Psychiatrist
Massachusetts Mental Health Center

John J. Mooney, M.D.
Assistant Professor of Psychiatry Harvard Medical School

Back To Top

Contact Us

Joseph J. Schildkraut, M.D. 617-731-2921

John J. Mooney, M.D. 617-731-2921

Patsy Kuropatkin 617-626-9463

Back To Top

Publications: Bibliography

Patent: Schildkraut JJ, Mooney JJ, inventors;
President and Fellows of Harvard College assignee. Antidepressant effect
of norepinephrine uptake 2 inhibitors and combined medications including
them. US patent 6,403,645. 2002 June 11.

Posener JA, Schatzberg AF, Williams GH, Samson JA, McHale NL, Bessette
MP, Schildkraut JJ. Hypothalamic-pituitary-adrenal axis effects on plasma
homovanillic acid in man. Biological Psychiatry 1999;45(2):222,228.

Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for comorbid
substance use disorder and schizophrenia: do patients with schizophrenia
have a reward-deficiency syndrome that can be ameliorated by clozapine?
Harvard Review of Psychiatry 1999;6:287-296.

Green AI, Drake RE, Zimmet SV, Strous RD, Burgess E, Xie H, McHugo G,
Khonstamm S, Schildkraut JJ. Alcoholism and schizophrenia: effects of
clozapine. Schizoprenia Research 1999;36(1-3):280-281.

Schildkraut JJ. The catecholamine hypothesis, interview by David Healy,
in
The Psychopharmacologists, Vol III, Oxford University Press, London, New
York,
2000, pp 111-134.

Canuso CM, Goldstein JM, Wojcik J, Dawson R, Brandman D, Klibanski A,
Schildkraut

JJ, Green AI. Antipsychotic medication, prolactin elevation, and ovarian
function in
women with schizophrenia and schizoaffective disorder. Psychiatry Research
2002; 111:11-20.

Back To Top

Omni Cleansing Drink Extra Strength Review

Nowadays, our body is constantly exposed to various forms of pollutants and toxins—from the air we breathe,
the food we consume, and even the water we drink. All these accumulate in our bodies and may sometimes cause
damage to our health. Those who wish to seek a solution for removing unwanted impurities from their systems
can use the Omni Cleansing Drink Extra Strength as a good alternative. Other options include Toxin Rid pills and a special detox drink called Detoxify Mega Clean. In this article, we go over the
details of Omni Cleansing Drink Extra Strength, how it actually works, and everything one needs to know
before trying it.

	#1 THC Detox Pills Toxin Rid Pills	Three-part detoxification system with pre-rid tablets, liquid detox, and dietary fiber The most popular product among customers 7 detox programs for ANY level of toxin exposure	See Deal →
	Urine Simulation Kit (Powdered Human Urine+Heater)	It’s real drug-free human urine For people who don’t have time for a detox All you need to pass a test in one pack: real urine powder, a medical vial, a temperature strip; two air-activated heaters It’s undetectable	CHECK THE DEAL →
	Mega Clean Drink + PreCleanse Pills	Effective for high toxicity levels Cleanses system within 3 hours! Urinary, circulatory, and digestive detox Works indiscriminately on all toxins	See Deal →

The Omni Cleansing Drink Extra Strength comes in a convenient 16-ounce bottle, and its formula is specially
designed to help users get rid of their body impurities quickly. It is recommended for people with a medium
body mass with average exposure to toxicants. Its refreshing Fruit Punch flavor has been commented on by
several users who enjoy taking it more than other detox products on the market.

Detoxing is a very important process in keeping one’s body healthy. People may argue that by eating clean
or working out every day, they can avoid toxins, but it’s nearly impossible to avoid the exposure of toxic
elements in some cases. Hence, products like the Omni Cleansing Drink and Detoxify Mega Clean will be apt to help your body flush out all the
toxins that are just unwanted guests in your body. The drink can, therefore, serve as a medium that can wash
away all these kinds of pollutants through your urine system and make you healthier or feel better.

In this review, we go through the ingredients of the product, its features, its effective usage, its pros
and cons according to customers, and some of the frequently asked questions. By the end of this article, you
should have an idea whether the Omni Cleansing Drink Extra Strength is right for you and how it can help you
reach your goal toward a cleaner, healthier body.

Product Description

This will surely help an individual in cleansing his or her body from unwanted toxins and pollutants with
the help of the Omni Cleansing Drink Extra Strength. The Omni cleansing drink is a product produced by Omni,
a company which manufactures health-related products. It is specially designed with formulated ingredients
and a user-friendly design. The bottle size is 16 ounces, easily carried and very convenient for people on
the go wanting to detoxify their systems.

The extra strength formula is the most appealing thing about this cleansing drink. That is to say, this
product is more potent in its action of giving your body faster results compared to the standard detox
drinks that are available in the market. This product is intended for people of medium body mass and with
moderate exposure to toxins, which applies to many people. Whether this be through exposure to environmental
pollutants, binging on foods that are bad for one, or maintaining health in general, this drink is aimed at
helping your body naturally detoxify.

Among the most valuable merits of the Omni Cleansing Drink, its great-tasting Fruit Punch flavor is
considered. Many users reported its pleasant taste makes it easier to consume compared with other detox
drinks, which sometimes can have an unappealing taste. This might turn out to be a big factor in deciding
whether to try this cleansing product or not, especially for those who tried something alike once but did
not enjoy the taste. We should say that Detoxify Mega
Clean also has different tastes aavailable.

The manufacturer recommends abundant consumption of water both before and after intake to increase the
efficiency of the Omni Cleansing Drink. Such hydration will keep the detoxification process running right
and ensure that such pollutants can be flushed out through one’s body. Moreover, urination at least three
times after drinking the drink is recommended by the company for fully expelling the toxins. This might
increase its effectiveness and lead to a successful cleanse.

Overall, the Omni Cleansing Drink Extra Strength is a great choice for anyone who wants an effective manner
of detoxification of the body. The effective formula, easy size, and good flavor go together to make this an
ideal choice for any given individual seeking to boost their health and well-being. In the subsequent
section, we shall take a look at what makes this effective in removing toxins from the body.

Ingredients List

Omni Cleansing Drink Extra Strength is a formulation made up of many ingredients combined and chosen for
their detoxification purposes. Further explanation will give a clear insight into how it really works, and
also explain its popularity among those keener to do a detox on their bodies. Detailed here are some of the
key ingredients generally found in the Omni Cleansing Drink:

1. Water
   The active ingredient in any detox drink, including the Omni Cleansing Drink and Detoxify Mega Clean, is water. Water becomes an essential ingredient
   to keep the body hydrated, an important aspect of detoxification. Good hydration dilutes toxins in the
   body and supports flushing them out through urine. That it has one asking to take more water before and
   after the application in order for cleansing to be fullest.
2. Herbal Extracts
   Many of these detoxification drinks, just like Omni, are actually conglomerations of herbal extracts that
   are known to clean the body. The common herbal ingredients may include dandelion root, milk thistle, and
   burdock root.
   • Dandelion Root: It is used in tradition as it supports the liver, allowing the body
     to filter out toxins a little more effectively.
   • Milk Thistle: It has protective effects against the liver; this ingredient
     encourages liver function and helps in detoxification.
   • Burdock Root: The root of the burdock plant is usually ingested for blood
     cleansing, whereby all wastes and toxins are filtered out of the bloodstream. The Omni Cleansing Drink
     may incorporate numerous vitamins and minerals to support the detoxification process. Components
     considered routine include:
3. Vitamin C: This vitamin possesses adequate quantities of antioxidants, which shield the
   body from oxidative stress, consequently strengthening immune response.
4. B Vitamins: B vitamins play an important role in energy metabolism and, therefore, can
   help the body make effective use of nutrition during the detoxification process.
5. Flavors and Sweeteners: The Omni Cleansing Drink adds natural flavors and sweeteners to
   enhance the taste. So does Detoxify Mega Clean.
   The Fruit Punch flavor is achieved by a combination of natural flavorings, which will make it a drink that
   one will enjoy consuming. Detox products must be pleasurable in terms of taste to sustain frequency,
   especially for first-time users.
6. Electrolytes: Some also have added electrolytes in the formula, such as potassium and
   sodium, which are responsible for regulating body fluids and preventing dehydration from the
   detoxification process. These are extremely vital in terms of the overall health of a person and may
   enhance performance on the physical aspects.

Taken together, these ingredients work in synergy in Omni Cleansing Drink Extra Strength to promote
detoxification and support the natural process of cleansing by the body. This product will help the user
feel revitalized and healthier because it rehydrates, supports liver function, and provides the body with
what it needs for nutrition. We are going to move on and explain how to use this product for the best
benefits to be obtained.

	#1 THC Detox Pills Toxin Rid Pills	Three-part detoxification system with pre-rid tablets, liquid detox, and dietary fiber The most popular product among customers 7 detox programs for ANY level of toxin exposure	See Deal →
	Urine Simulation Kit (Powdered Human Urine+Heater)	It’s real drug-free human urine For people who don’t have time for a detox All you need to pass a test in one pack: real urine powder, a medical vial, a temperature strip; two air-activated heaters It’s undetectable	CHECK THE DEAL →
	Mega Clean Drink + PreCleanse Pills	Effective for high toxicity levels Cleanses system within 3 hours! Urinary, circulatory, and digestive detox Works indiscriminately on all toxins	See Deal →

How to Use the Product

Correct use of Omni Cleansing Drink Extra Strength will ascertain that its action for detoxification is
realized to the fullest. Here is a step-by-step guide on how one can use this product efficiently to clean
his system.

1. Shake Well
   It must be well shaken before drinking. This rule applies to Detoxify Mega Clean as well. This will ensure proper mixing and equal
   distribution of all ingredients throughout the drink. Proper mixing is advisable because it will enhance
   the effectiveness of the ingredients, so that they can work synergistically during the detoxification
   process.
2. Drink the Entire Contents
   Following the shaking, take the entire drink in a 16-ounce bottle. One has to drink all of it at once for
   effectiveness. This rapid intake will allow the active ingredients to start working together in your body
   right away without the loss of any time.
3. Pre- and post-hydration
   Of course, hydration is a significant part of any detox process. After having the Omni Cleansing Drink,
   one is supposed to drink plenty of water. In fact, the manufacturer specifically states that you should
   take at least 16 ounces of water before the detox drink and keep hydrating well after. Adequate hydration
   will facilitate your body’s process of eliminating toxins with ease and also ensure that your kidneys will
   be able to function effectively during the detox process.
4. Fast for Three Hours
   A person is advised not to take any kind of food three hours before the Omni Cleansing Drink and remain
   without solid foods in this period of less-than-toxic cleaning. This would provide your system with a
   better opportunity to discard these toxins without interference that may come from the digestion of food.
   This provides it the capability to function well without the additional burden of meal processing.
5. Urinate Frequently
   After intake of any detox drink, including Detoxify
   Mega Clean, one must urinate at least three times. This is quite an important part of eliminating
   toxins from the body. Your body is being subjected to the elimination of pollutions through urinating,
   which is what the Omni Cleansing Drink has taken initiative on removing from your system. When frequent
   urination occurs, it shows that the process of detoxification is going well and also gives a needed push
   towards being totally free from such toxins.
6. Monitor Your Body
   Pay attention to how your body feels during and after using the drink. It is normal that you are going to
   urinate more frequently, and you may have some minor discomfort as toxins leave your body. However, in
   cases of extreme side effects or unnatural symptoms that might appear in your body, this product use has
   to be immediately stopped, followed by a consultation of a professional healthcare provider.

The steps highlighted above will, no doubt, facilitate the best results if adhered to in the course of
using Omni Cleansing Drink Extra Strength. In fact, effective preparation, hydration, and awareness of your
body’s reaction are the surefire keys towards a successful detox experience. Next, we shall look into some
pros and cons based on customer feedback to present a balanced view regarding the effectiveness of the
product.

Product Pros and Cons

As far as the Omni Cleansing Drink Extra Strength is concerned, the pros and probable cons revolve around
weighing the benefits and drawbacks from customers who have reviewed the product. Below are some positive
and negative reviews about this detox drink to inform you before making up your mind.

Pros

• Effective Detoxification: Many customers have reviewed that the Omni Cleansing Drink
  helps them get rid of toxins within their bodies. It is gratifying to think that the extracts of herbs and
  hydration can combine in such a manner as to assist in a cleaning process so effective, as far as uptakes
  in energy and a whole sense of well-being.
• Great Taste: The Fruit Punch flavor of the drink is well-appreciated by its users. Many
  report that it’s a pleasure to drink, which could be a big factor for users who are apprehensive about
  trying detox products due to previous experiences with bad-tasting products. The great taste will make the
  user most likely continue with the product.
• Ease of Use: Directions for ease of use for the Omni Cleansing Drink make the product
  obtainable for all. For this detox drink, like any other detox drink, just a few steps are needed: shake
  the bottle, drink what is inside, and then drink much water. After all that, everything will be rather
  easy for them.
• Quick Results: The Extra Strength formula offers appealingly quick results to many.
  Many say that mere hours after intake, one can start feeling the detoxifying effects of it, which can be
  so relieving to people who want a quick cleanse. Detoxify Mega Clean also works extremely fast
• Healthy Lifestyle Supportive: The Omni Cleansing Drink agrees with being
  health-conscious. For people who eat clean and exercise well, this can be a good help to make their bodies
  free of toxins.

Cons

• Limited Effectiveness for Heavy Users: Some users comment on the fact that the Omni
  Cleansing Drink may not be as efficient in the case of users who have been exposed to high levels of
  toxins, such as regular users of alcohol or drugs. It is intended for moderate toxin exposure, and users
  with higher exposure may require further assistance or other detoxification methods.
• Temporary Solution: Some users feel that the detox effects may be temporary; it was
  able to take out toxins from the body but failed to provide a lesson in lifestyle changes to avoid toxin
  buildup in the future. Because of this fact, they have to repeatedly use it to detoxify continuously,
  which becomes too costly for them. However, you can use Toxin Rid pills to fully detox your body and achieve consistent
  results.
• Possible Side Effects: While most report no possibly positive side effects from taking
  it, there have been individuals who have experienced mild side effects, including stomach discomfort or
  higher urination. This would be determined by the individual’s tolerance and quantity or level of toxin
  exposure. It is therefore important to listen to your body and seek medical attention should any adverse
  reactions occur.
• Not to Replace Wholesome Nutrition: Although the Omni Cleansing Drink has proven very
  helpful as a detox tool, it is not to be considered one to replace healthy nutrition and a decent life
  course. If one remains completely dependent on detox drinks without making too many changes in one’s life,
  then the results will not be optimal.
• Affordability and Availability: Depending on your geographical location, finding an
  Omni Cleansing Drink could be a real pain in the neck. In addition, if you plan on using such detox drinks
  frequently, rest assured that the cost could add up. Therefore, for budget-conscious consumers, price may
  turn out to be a deciding factor for the incorporation of such a product into one’s regimen.

The benefits that result from the Omni Cleansing Drink Extra Strength include efficient detoxification and
great taste, hence a commendable option for anyone wanting to cleanse his or her body. This option, however,
has its limitations, especially for people with higher toxin exposure and those seeking long-term solutions.
Toxin Rid pills will work perfectly for the latter
group, though. Understanding these pros and cons will bring you closer to whether this detox drink is the
right decision to make in respect of your health goals. The next section will cover some frequently asked
questions with the intention of providing further clarity on the product and its use.

Frequently Asked Questions

For further clearance of the Omni Cleansing Drink Extra Strength, herein are some frequently asked
questions together with their answers:

How many times a day can I take the Omni Cleansing Drink Extra Strength?

According to the manufacturer, the Omni Cleansing Drink should be used only when necessary for
detoxification. Still highly suggested is at least 30 days between uses so your body can heal and go back to
its natural detoxification process. Not allowing time in between doses can render it not as effective and
can also put extra stress on your system that it doesn’t need.

Is the Omni Cleansing Drink safe for all users?

The Omni Cleansing Drink is generally safe for most adults. Any detoxification program, though, really
should first be discussed with a healthcare professional if an individual has some type of illness or is
pregnant/breastfeeding. Mild side effects may be associated with its use, and for that, professional advice
can be sought as to whether it will be suitable or not in your particular case.

What do I do in case of bad condition after the use of the drink?

In case of side effects like nausea, heavy stomach aches, or any kind of dizziness after consumption of the
drink, one must stop using it immediately and consult for medical advice. In such a case, the call of your
body is to be listened to, and through which medical advice may come.

Can I eat food while using the Omni Cleansing Drink?

It is not advisable to consume solid foods at least three hours prior to and during the course of the
cleansing program for better results. This rule works for Detoxify Mega Clean as well. This will ensure that the action of the
drink is not interfered with by digestion. You can start eating after the detox, gradually introducing
healthier, cleaner food into your body.

	#1 THC Detox Pills Toxin Rid Pills	Three-part detoxification system with pre-rid tablets, liquid detox, and dietary fiber The most popular product among customers 7 detox programs for ANY level of toxin exposure	See Deal →
	Urine Simulation Kit (Powdered Human Urine+Heater)	It’s real drug-free human urine For people who don’t have time for a detox All you need to pass a test in one pack: real urine powder, a medical vial, a temperature strip; two air-activated heaters It’s undetectable	CHECK THE DEAL →
	Mega Clean Drink + PreCleanse Pills	Effective for high toxicity levels Cleanses system within 3 hours! Urinary, circulatory, and digestive detox Works indiscriminately on all toxins	See Deal →

Does the Omni Cleansing Drink work when it comes to passing a drug test?

Some users report their success using detox drinks like Omni for helping with clearing their systems, while
the effects may vary in accordance with a number of factors, including one’s metabolism, body mass, and the
quantity/level of toxin exposure. Keep in mind that there is no fully guaranteed method of passing a drug
test, and to depend on detox drinks is highly risky. Always consider the possible aftermath and look toward
safer, legal means of health and wellness. We also recommend using synthetic urine like Urine Simulation with Powdered Urine Kit if you
have to pass a surprise urine drug test and don’t have enough time to properly prepare for it.

Is any form of alcohol allowed during the Omni Cleansing Drink?

It is highly advisable to avoid all types of toxins, especially those related to alcohol and tobacco, for
some time before and during the course of action with the Omni Cleansing Drink. Alcohol consumption would
interfere with the working process of detoxification and reduce its effectiveness. For better results, focus
on hydrating yourself and engaging in healthier activities during your cleansing cycle.

What if I don’t pee after using the drink?

Urination plays a significant role in detoxification when using the Omni Cleansing Drink. If you feel that
after consumption you did not get the urination as anticipated, it may be your body not eliminating the
toxins properly. Make sure you are well hydrated and pay attention to the responses of your body. If the
situation prevails, then one may consult a doctor for advice on how to go ahead with the detox process.

Summary

The Omni Cleansing Drink Extra Strength will definitely help you cope with every unwanted pollutant and
toxin in your body. The usage instructions are very easy, and the product has a fruity taste, similar to
Fruit Punch, which makes it viable for all customers by offering fast-acting detox support.

• Detoxify Effectively: The formula is designed in such a way that it will help in the
  elimination of toxins, and for that reason, it may be very effective for people with moderate toxin
  exposure. Many reported that they could feel the benefits of detoxification within a few hours of its
  usage.
• Easy to Use: The instructions of use with Omni Cleansing Drink are simple: shake,
  drink, hydrate, and urinate. The process of hydrating will play an important role in toxic elimination
  from your body effectively.
• Pros and Cons: While the drink is going to provide a lot of benefits, such as great
  taste and speed of action, it may not be so effective in the case of heavy users or for people with a high
  level of toxins in the system. We recommend such individuals to rely on Toxin Rid pills instead. Also, it should be treated not as the
  ultimate solution but only as one tool among the means that will help keep up with a healthy lifestyle in
  general.
• Q&A Insights: This was an enlightening section that answered some of the frequently
  asked questions on the importance of being aware of individual reactions towards the product, proper usage
  guidelines, and when one should consult a doctor in case something goes wrong.

In conclusion, the Omni Cleansing Drink Extra Strength can prove to be quite helpful for those undergoing a
detox course and for health-conscious individuals who would want to rid their body of toxins periodically.
However, for this to be most effective, usage has to combine with proper diet and healthy lifestyle. Always
consult with a health professional regarding your health or detox product usage. With a better understanding
and application of these principles, you can experience more fulfilling well-being and encourage a cleaner,
healthier body.

Harvard Department of Psychiatry
at Massachusetts Mental Health Center
and The Massachusetts Mental Health Institute
Announce the Availability of
Research Fellowships
July 1, 2002 – June 30, 2004

Successful candidates must hold the M.D. or Ph.D. degree and will work under the supervision of Faculty Members in the Harvard Medical School Department of Psychiatry at the Massachusetts Mental Health Center.

Priority will be given to those applicants interested in the following areas of research:

• Clinical Psychopharmacology (Carl Salzman, MD)
• Cognitive Neuroscience of Sleep and Dreaming (J. Allan Hobson, MD)
• Forensic Psychiatry (Thomas G. Gutheil, MD)
• Homelessness and Stigma (Robert M. Goisman, MD)
• Neuropsychology and Neuroimaging (Larry J. Seidman, PhD)
• Psychiatric Epidemiology and Genetics (Ming T. Tsuang, MD, PhD)
• Psychobiology of Psychosis (Alan I. Green, MD)
• Psychobiology of Major Affective Disorders (Joseph J. Schildkraut, MD)
• Gender Differences in the Brain & Psychopathology (Jill M. Goldstein, PhD)

Please submit C.V. and letter of intent to Dr. Allan Hobson, Massachusetts Mental Health Center, 74 Fenwood Road, Boston, MA 02115, USA, no later than
December 31, 2001. Letter of intent should indicate familiarity with one of the areas listed in the above-cited priority section and present an outline of project goals for further discussion with your prospective mentor.

Coming Soon