My dear colleagues and friends,
I am honored to have the privilege of delivering this oration before such an august
gathering. I wish to pay my respects to the memory of the late Professor DLN Murthy
Rao in whose name this oration was instituted. I thank my parents for their unwavering
belief and support which nourished me during my formative years. I acknowledge with
deep gratitude the influence of my teachers who, in more ways than just through education,
were instrumental in shaping my growth. And, I place on record my indebtedness to
the National Institute of Mental Health and Neurosciences, Bangalore, the institute
which provided me with the opportunity to blossom in my career.
It is customary for the recipient of this award to showcase his research and to discuss
its impact on the field. I am aware that I am best known for my work on electroconvulsive
therapy (ECT) and psychopharmacology, especially in the context of animal models of
investigation. However, listeners may be surprised and even amused to learn that,
with the assistance of able students, colleagues, and collaborators at my institute
and elsewhere, my fields of enquiry have been varied and wide. I am a curious person
by nature and strongly believe that science knows no boundaries; if a question is
worth asking, it is worth studying. As a result, in addition to ECT, I have worked
and published in clinical psychopharmacology,[1–20] preclinical (basic science) psychopharmacology,
[21–35] herbal medicine,[1
4
9
30
36–48] psychiatric phenomenology, [49–58] bipolar disorders,[8
11–13
56
59–65] statistics and research methodology, [66–76] family psychiatry[77–84] and fields
such as environmental medicine, neuropsychology, education, and even snakebite.[85–92]
My interest in these diverse areas persists to this very day. For those who may be
curious, I have cited some representative references in this article; readers who
would like a complete bibliography, or who desire reprints of specific articles, may
write to me.
Without a shadow of doubt, an interest in ECT dominated my research during the past
twenty-five years. Subjects that my colleagues and I addressed related to the history[93]
and practice[94–96] of ECT; the efficacy[97–116] and adverse effects of the treatment
in clinical and preclinical contexts;[117–126] methods and schedules of administration
of ECT;[127–131] knowledge about, attitudes towards, and experiences with ECT;[132–142]
and even literary issues.[143]
FIELDS OF SPECIAL INTEREST
Four areas seized our especial interest: the use of herbal medicines in the attenuation
of the cognitive adverse effects of ECT,[38–47] the mechanism of action of ECT,[144–151]
electrical aspects of ECT[97
98
127
151–165] and the safety and efficacy of unmodified ECT;[166–172] we addressed these
areas as independent as well as interacting entities. I summarize our findings in
the passages that follow. For clarity in communication, I will use the generic term
‘ECT’ to refer to both electroconvulsive therapy (in humans) and electroconvulsive
shocks (in animal models).
Herbal medicines for the cognitive adverse effects of ECT
ECT induces anterograde and retrograde amnesia, as well as non-memory cognitive deficits.
The amnestic deficits of ECT have been well characterized; whereas anterograde amnesia
is mild and temporary, retrograde amnesia for autobiographical and nonautobiographical
memories is frequent, and may be severe in a small proportion of patients; memories
of lesser emotional salience are more vulnerable to loss. Although there is no evidence
that ECT results in brain damage, and although there is evidence that ECT stimulates
neuroplasticity and related changes in structures such as the hippocampus, amygdala,
and prefrontal cortex, the use of electricity, the triggering of a seizure, and the
cognitive adverse effects of the treatment are together responsible for the treatment
being held in distrust.[134] To this extent, at least, the acceptability of ECT could
improve should it prove feasible to contain the cognitive adverse effects without
compromising the efficacy of the treatment.
Herbal medicines receive marketing approval in India without need for evidence of
safety and efficacy.[46] We initiated a program to determine whether herbal treatments
with putative neuroprotective effects could limit ECT-induced amnestic deficits. We
used several different animal models of anterograde and retrograde amnesia in our
experiments and obtained encouraging results with a complex herbal formulation,[38–42]
with a simplified herbal formulation,[44–45] with the individual herbs Brahmi and
Mandookaparni, separately and in combination,[47] but not with an aqueous extract
of Shankapushpi.[43] Our findings have been summarized elsewhere along with a critical
appraisal of the field, and a commentary on animal models and caveats concerning generalization
from laboratory to clinical contexts.[46] Regrettably, as a result of a lack of funding,
we were unable to do the translational research necessary to examine the safety and
efficacy of herbal formulations in humans who are treated with ECT for psychiatric
disorders; however, we did demonstrate that one formulation attenuates age-related
cognitive decline in a community-based population.[1] The field remains open for further
investigation.
The mechanism of action of ECT
Today, so much is known about the mechanism of action of ECT that it would take a
book to review the field. Our contribution to this area has been small. Using animal
models, we showed that ECT downregulates dopamine autoreceptors and alpha-2 adrenoceptors,
and upregulates dopamine postsynaptic receptors, thereby facilitating both dopaminergic
and noradrenergic neurotransmission.[144–149
151] Importantly, for the first time in literature, we showed that maintenance ECT
maintains the alpha-adrenergic receptor change[149] and also that high but not low
dose electrical stimuli elicit the dopamine postsynaptic receptor upregulation that
is seen with ECT.[151]
Electrical aspects of ECT
Medications are dosed in terms of weight of the active ingredient. In ECT, the active
ingredient is electricity. Curiously, most practitioners dose ECT in terms of the
number of treatments administered; this is like asking patients to take a certain
number of tablets without regard to the strength of the pill. Work by Sackeim and
his colleagues, starting from the late 1980s, established that higher electrical doses
with reference to the seizure threshold increase the likelihood of response in patients
who receive unilateral ECT, and increase the speed of response whatever the electrode
placement.[173–175] This encouraged us to probe deeper into electrical aspects of
ECT.[97
98
127
151–165]
The stimulus in brief-pulse ECT is made up of four elements: pulse amplitude, pulse
width, pulse frequency, and stimulus duration. These four elements can be combined
in different ways to yield the same charge; that is, the same electrical dose. But,
there is no assurance that differently constituted charges have identical biological
effects.[155] In a tightly controlled study conducted in an animal model, we furnished
unequivocal evidence that the seizure threshold is a variable point, and that, at
constant electrical charge, it is lower when the electrical stimulus train duration
is longer.[157] The importance of this study was underlined when the Association for
Convulsive Therapy, USA, honored it with the ECT Investigator of the Year Award at
its annual conference in San Francisco, during 2003.
In another study with far-reaching implications, we used power spectral electroencephalogram
(EEG) analysis in an animal model to demonstrate how differently constituted electrical
stimuli that were identical in charge could nevertheless differ in therapeutic efficacy
and in adverse effect potential. We found that a narrow pulse width associated with
high pulse frequency, especially in combination with a long stimulus train, were associated
with three different EEG proxies of seizure efficacy: greater ictal power, greater
postictal suppression, and greater interictal power, particularly in the lower frequency
bands. In contrast, greater pulse width and lower pulse frequency showed no such associations.
Stimulus-on time, number of pulses delivered, and rate of delivery of charge did not
predict efficacy.[159] These findings could have much influence on the way ECT charges
are constituted in clinical contexts. Clinical research on narrow pulse widths is
now being pursued by several teams with encouraging results.
A chance observation during our work on the ECT seizure threshold led us to a dramatic
new finding in neuroscience: that subconvulsive stimuli delivered to the brain lower
the seizure threshold on subsequent days. In other words, the brain as a whole appears
to respond more readily with a seizure discharge if previously primed with subconvulsive
stimuli.[161] We confirmed this kindling effect in a controlled study.[162] Although
we labeled the phenomenon ‘whole-brain kindling’, we later noted that what was actually
kindled was probably only the brain territories involved in the triggering of the
seizure.[163]
Unmodified ECT
In a 1991 survey of the Indian Psychiatric Society, we found that only 44% of respondents
to a postal questionnaire invariably administered modified ECT.[95] Our initial response
was one of shock and indignation.[95
166] However, in an observational study,[167] we found that, notwithstanding the 20-40%
incidence of musculoskeletal complications with unmodified ECT in historical Western
studies, only 1 of 50 patients who received a course of 6 unmodified treatments actually
experienced a spinal complication (which turned out to be subclinical). We subsequently
revised our stance to the cautious position that modified ECT is desirable, but in
exceptional circumstances unmodified ECT may be better than no ECT. We also examined
issues related to ethics, and the definition of what might constitute exceptional
circumstances for a country such as India.[168–171] In our most recent study, we confirmed
our finding that musculoskeletal complications with unmodified ECT are rare in Indian
patients, and suggested that benzodiazepine-modification of the seizure (resulting
in drug-induced muscle relaxation) may be one of several explanations for our unexpected
findings.[172]
MECHANISMS UNDERLYING ECT-INDUCED AMNESTIC DEFICITS
Returning to the subject of our earlier research,[38–47] we reasoned that if we could
understand what mechanisms explain ECT-induced amnestic deficits, we might be able
to better develop treatments to diminish such deficits. Our lines of investigation
followed two paths: we studied whether attenuating the systolic blood pressure surge
during ECT results in decreased cognitive adverse effects[176–180] and we investigated
the involvement of specific neurotransmitter mechanisms in ECT-induced amnestic deficits.[181–184]
Curiously, two of the blood pressure surge studies themselves suggested neurotransmitter
mechanisms.[177–178]
Hypertensive surge and cognitive impairment with ECT
It has long been known that there is a sharp surge in systolic blood pressure during
the ECT seizure.[180] Hypothetically, this surge may breach the blood-brain barrier,
causing hyperperfusion-related mild cerebral edema as well as a leak of proteins and
other macromolecules into the CSF and interstitial spaces in the brain. These changes
may disturb neuronal functioning, predisposing to cognitive impairment.[179] We reviewed
the clinical literature on the subject and found some support for this hypothesis.[176]
Accordingly, we used an animal model to study whether the calcium channel blockers
verapamil and felodipine, administered shortly before ECT, can reduce the amnestic
deficits of the treatment. We chose both verapamil and felodipine because both belong
to the same category of drug; and because the latter has only peripheral action.
In this study,[176] we demonstrated that just two once-daily ECT sufficed to induce
retrograde amnesia in rats trained in the Hebb-Williams maze; verapamil or felodipine,
administered half an hour before each ECT, attenuated this amnesia. On the surface,
these finding support our hypothesis. However, we realized that other mechanisms could
also have been be involved: cerebral vasodilatation, enhancement of cholinergic tone,
and inhibition of calcium-mediated excitotoxic impairment of neuronal functioning.
In order to further investigate our hypothesis, we studied the effects of a different
antihypertensive agent: sodium nitroprusside[177] and we separately asked whether
increasing blood pressure, using phenylephrine, worsens amnestic deficits with ECT.[178]
We found that three once-daily ECT successfully induced retrograde amnesia in a passive
avoidance task, and that the pre-ECT administration of nitroprusside, despite increasing
the seizure duration, reduced the severity of this amnesia. Unexpectedly, nitroprusside
also improved recall in control rats which did not receive ECT.
What do we make of these results? Nitroprusside may have attenuated the amnesia by
reducing the systolic blood pressure surge during ECT. But, nitroprusside may also
have worked by other mechanisms, such as by improving cerebral perfusion through vasodilatation.
And, nitroprusside is a nitric oxide donor, and nitric oxide mechanisms are known
to facilitate learning and memory. Most importantly, the improved recall in control
rats suggested that nitroprusside could have nonspecific effects on cognition that
are independent of ECT and the blood-brain barrier breach mechanism. As a result,
these findings[177] again left us without a firm conclusion.
So, we moved to the phenylephrine study.[178] Phenylephrine is a nonselective alpha
receptor agonist which can be expected to raise blood pressure. We examined whether
the administration of phenylephrine immediately before ECT would increase ECT-induced
amnesia. As before, we found that three once-daily ECT induced retrograde amnesia
in a passive avoidance task. Surprisingly, (and even more so because we found that,
like nitroprusside, it increased seizure duration), phenylephrine attenuated the ECT-induced
amnestic deficits. An additional unexpected finding was that phenylephrine also improved
recall in rats which received sham ECT. This led us to conclude that the adrenergic
effects of phenylephrine nonspecifically improved memory functioning; in this context,
adrenergic mechanisms have long been known to facilitate memory consolidation and
storage. Since phenylephrine increases blood pressure, our most recent findings weakened
the hypothesis that ECT-induced cognitive impairment is a consequence of cerebral
edema and blood-brain barrier breach resulting from the intra-ECT hypertensive surge.
However, it remained possible that the adrenergic cognitive-facilitatory mechanisms
of phenylephrine could have more than counterbalanced the hypertensive surge cognition-disturbing
mechanisms of ECT as augmented by the drug.
A limitation of these experiments is that we did not actually measure blood pressure
changes with the drugs that we administered. Nevertheless, the findings that nitroprusside,
phenylephrine, and calcium channel blockers attenuate ECT-induced amnestic deficits
are still positive results worthy of clinical examination. As far as the hypertensive
surge hypothesis is concerned, the field remains open for further study.
Glucocorticoid mechanisms and ECT-induced amnesia
The hippocampus and the amygdala are both involved in learning and memory, and neurons
in both structures richly express glucocorticoid receptors. Physiological activation
of these receptors facilitates long-term potentiation (LTP) and neuroplasticity; that
is, mechanisms which represent the cellular basis of learning and memory. However,
excessive glucocorticoid stimulation (such as due to hypercortisolemia resulting from
chronic stress, chronic depression, Cushing's syndrome, or the administration of exogenous
steroids for therapeutic purposes) has been shown to induce a loss of dendritic spines
and synapses, shrink the hippocampus, and impair cognition in both animal models and
humans.[185]
Our review of literature[182] showed that ECT results in a hypercortisolemic surge
that, though transient, lasts for hours after the seizure. Could this surge be responsible
for the cognitive adverse effects of the treatment? Could blunting this surge attenuate
ECT-induced cognitive impairments? We investigated the subject using the abortifacient
drug mifepristone as an in vivo probe. In parentheses, mifepristone is used in gynecological
practice because it is a competitive progesterone receptor antagonist; but mifepristone
is also a highly potent glucocorticoid receptor antagonist. If ECT-induced hypercortisolemia
stimulates hippocampal neurons physiologically, the transient hypercortisolemia could
be a natural though incompletely effective defense against ECT-induced cognitive impairment;
if so, mifepristone would worsen ECT-induced amnesia. But, if ECT-induced hypercortisolemia
stimulates hippocampal neurons to a pathological degree, it would contribute to ECT-induced
cognitive impairment; if so, mifepristone would reduce amnestic deficits with ECT.
As we had done earlier, we investigated the matter in an animal model. We administered
mifepristone in two different doses (20 mg/kg/day and 40 mg/kg/day) one hour before
each of five once-daily ECTs to rats that had been trained in a passive avoidance
task. We tested recall a day after the last ECT. A part of our results is presented
in Figure 1. ECT resulted in retrograde amnesia in the control but not in the mifepristone
groups. The higher dose of mifepristone was associated with significantly better recall
scores relative to the control group. Thus, mifepristone clearly protected against
ECT-induced retrograde amnesia. This implicates the ECT-induced hypercortisolemic
surge (with consequent overstimulation of glucocorticoid receptors) as one mechanism
of ECT-induced amnestic deficits, and suggests that glucocorticoid mechanisms can
be modulated to protect against the development of these deficits.
Figure 1
Mean recall scores in control and mifepristone (20mg/kg/day and 40 mg/kg/day) groups
after five oncedaily ECT (lower scores indicate poorer recall; that is, greater retrograde
amnesia). There was significant amnesia in the control but not mifepristone groups;
recall scores were significantly higher in the mifepristone 40 mg/kg/day (but not
20 mg/kg/day) group relative to the control group
ECT and glutamateric excitotoxicity: A role for NMDA receptor, COX-2, and kynurenic
acid modulation in ECT-induced amnesia
We next attempted something more ambitious: the study of the role of glutamatergic
neurotransmission at the N-methyl D-aspartate (NMDA) receptor site, along with cyclooxygenase-2
(COX-2) and kynurenic acid lipid signalling mechanisms, in ECT-induced retrograde
amnesia. Our work on this subject began with the well-known observation that chronic
treatment with antiinflammatory drugs such as indomethacin in conditions such as rheumatoid
arthritis is associated with a decreased risk of Alzheimer's disease; we therefore
examined the neuroprotective effects of indomethacin and were pleasantly surprised
to find that this drug reduced the severity of ECT-induced amnesia.[181] Indomethacin,
however, is COX-nonselective and is, in fact, more effective against COX-1 than against
COX-2; this is a negative for the drug because COX-2 is more important in learning
mechanisms than COX-1.[183] Our review of literature[183] also showed that indomethacin
increases kynurenic acid levels whereas COX-2 selective drugs such as celecoxib decrease
kynurenic acid; as kynurenic acid dampens neurotransmission at all ionotropic glutamatergic
receptor sites, and as glutamatergic neurotransmission is fundamental to LTP and neuroplasticity,
celecoxib could be expected to demonstrate greater neuroprotective efficacy than indomethacin.
Normally, glutamate released during learning stimulates the NMDA receptor, launching
a cascade of downstream events [Figure 2]. These events include activation of COX-2
and thence a conversion of membrane arachidonic acid to endogenous prostanoids, as
well as a conversion of endogenous cannabinoids (which dampen NMDA signalling) into
novel prostaglandins (which increase NMDA activity). These events also include the
activation of platelet activation factor (PAF). The COX-2 and PAF activation result
in feedback augmentation of the NMDA signal. Other reverberating circuits (including
those that involve retrograde neurotransmission through arachidonic acid) that amplify
the NMDA signal also develop.[183
184] The net effect is glutamate- and NMDA-dependent initiation of LTP in the hippocampus,
and thence the hardwiring of learning and memory through neuroplasticity changes.
Figure 2
Glutamatergic mechanisms in learning, memory, and ECT-induced amnesia, and the europrotective
mechanisms of indomethacin and celecoxib herein
Glutamatergic signaling is pathologically upregulated due to massive neuronal discharge
during the ECT seizure. This may hypothetically result in a saturation of the cellular
mechanisms that are responsible for hippocampal LTP and hence a decreased opportunity
for the recruitment of these mechanisms for new learning. The consequence is ECT-induced
amnesia.[183] Increased neuronal activity during the ECT seizure could additionally
result in oxidative stress, and in an osmotic influx due to excessive (NMDA-mediated)
entry of calcium into the cell; oxidative stress and osmotic load could both further
contribute to ECT-induced cognitive impairment [Figure 2].
Under physiological conditions, COX-2 inhibitors inhibit learning and memory by dampening
NMDA signaling. However, administration of COX-2 inhibitors pre-ECT could prevent
glutamatergic excitotoxicity by blocking at least some of the reverberating circuits
[Figure 2]; as a result, there could be less osmotic influx, less oxidative stress,
and less saturation of LTP mechanisms. In consequence, ECT-induced amnesia may diminish.
Based on the model that we constructed (simplified in Figure 2), we hypothesized that
celecoxib would outperform indomethacin in this regard because, unlike indomethacin,
celecoxib would decrease kynurenic acid, thereby facilitating normal NMDA signalling
after the seizure.[183]
We again conducted our studies in an animal model. We administered indomethacin (4
mg/kg/day) or celecoxib (15 mg/kg/day) to rats that received five once-daily ECT.
We tested recall of passive avoidance learning a day after the last ECT. A part of
our results is summarized in Figure 3. ECT resulted in retrograde amnesia in the control
but not in the indomethacin and celecoxib groups. Whereas indomethacin partly protected
against ECT-induced amnestic deficits, retrograde amnesia was completely prevented
in the animals which received celecoxib. These findings support the model that we
constructed [Figure 2] and suggest that glutamatergic and COX-2 mechanisms can be
modulated to protect against ECT-induced retrograde amnesia in clinical contexts.
In parentheses, interested readers would do well to read our studies in the original
for a more detailed exposition of the mechanisms involved.
Figure 3
Mean recall scores in control, indomethacin (4 mg/kg/day), and celecoxib (15 mg/kg/day)
groups after five once-daily ECT (lower scores indicate poorer recall; that is, greater
retrograde amnesia). There was significant amnesia in the control but not indomethacin
and celecoxib groups; recall scores were significantly higher with celecoxib (but
not indomethacin) relative to controls.
WHERE DO WE GO FROM HERE?
As we described in an extensive review, we now know a great deal about the mechanisms
underlying ECT-induced amnestic deficits[126] and there are extensive animal data
to suggest pharmacological approaches towards the prevention of such deficits. Our
own work suggests that certain herbal formulations, certain antihypertensive drugs
(especially the calcium channel blockers), the glucocorticoid antagonist mifepristone,
and certain antiinflammatory agents (especially the COX-2 inhibitors) justify further
study in this regard. More specifically, translational research is now necessary to
identify whether the findings from the laboratory can be extrapolated to the clinic.
Concluding notes
This has been a long journey, but there are still miles and miles to go. I am conscious
that I cannot alone do all that is left to do. I am conscious that there is a large
pool of talent in this country that is looking for direction in researching important
questions in psychiatry and psychopharmacology. I now wish to devote a greater proportion
of my time to the development of research talent so that ambitious students and academicians
in this country can feature more prominently on the global map. From my experience
during the past few years, I have come to realize that possibly the only model which
will succeed in this goal is one that is based on the academic institute. It would
give me much pleasure to provide interested institutes in this country with training
in research methods and statistics; to provide research questions and methodologies
for the study of these questions; and to provide backup support for data analysis
and report writing. If at the end of these exercises Indian psychiatry grows stronger
in research capacity, my efforts would not have been in vain.