INVITED REVIEW
The Antipsychotic Effects of ECT A Review of Possible Mechanisms
Peter B. Rosenquist, MD, Brian Miller, MD, MPH, PhD, and Anilkumar Pillai, PhD Objectives: Electroconvulsive therapy (ECT) exhibits demonstrable effectiveness for psychotic symptoms associated with a broad range of neuropsychiatric conditions. However, the mechanism remains poorly understood particularly with regard to antipsychotic effects. Methods: We examined studies of ECT in schizophrenia and mood disorders, as well as from animal models of psychotic disorders, and compared the results to those of antipsychotic medications. This review focuses on 3 potential domains of exploration of ECT’s antipsychotic effects: dopamine and serotonin neurotransmitter activity, neurotrophic effects, and immune system modulation. Results: Preliminary results support a putative role for all three of these domains but are limited by a lack of replicated findings, including negative studies. Conclusions: A comparison of the neurophysiologic and molecular properties of antipsychotic drugs and ECT reveals some overlap, but there are also distinctive differences; and the significance of these findings remains uncertain. Key Words: ECT, antipsychotic drugs, mechanism of action, cytokines, brain-derived neurotrophic factor (J ECT 2014;30: 125–131)
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ince the inception of ECT, patients and practitioners have wondered, “How does it work?” Despite keen interest, the mechanisms of action underpinning the remarkable and broad therapeutic effectiveness remain poorly understood. In this regard, very little inquiry has focused specifically on the antipsychotic effects of ECT, perhaps mirroring clinical practice in the treatment of schizophrenia as the archetypal psychotic disorder. For most of the Western hemisphere, ECT is largely considered a treatment for major depression and bipolar disorder and is rarely used to treat schizophrenia, its use having declined since the 1960s with the advent of effective antipsychotic medication.1 However, in Eastern nations such as India, China, parts of Africa, and other developing countries, ECT is viewed as a first-line treatment of severe psychosis when symptoms require hospitalization. Similarly, in the case of the secondary psychoses associated with other neuropsychiatric conditions and drug-induced states, ECT is used second line for treatment-resistant cases. The literature for these conditions is therefore limited to smaller studies, case reports, and case series, which serves to hinder systematic inquiry into mechanisms of action. Nevertheless, ECT has demonstrable antipsychotic effects, which can be observed across a number of conditions, most notably in mood disorders with accompanying psychotic features, and is being reconsidered as a viable option in treatment-resistant schizophrenia.
From the Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, Augusta, GA Received for publication February 18, 2014; accepted March 11, 2014. Reprints: Peter B. Rosenquist, MD, Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, 997 St Sebastian Way, Augusta, GA 30912 (e‐mail: [email protected]). The authors have no conflicts of interest or financial disclosures to report. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/YCT.0000000000000131
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Consistent with its broad spectrum of efficacy, we assume for the purposes of this review that ECT induces widespread and multidimensional neurophysiologic changes within the brain. Additional axioms are that the pathophysiologic state influences, and is influenced by, ECT. Therefore, ECTs demonstrated effects in nonpsychotic states may or may not be applicable to psychotic states. Finally, it is presumed that only a subset of the many ECT-induced changes in brain function, structure produce clinical improvement, and are as likely to be compensatory as directly responsible for reversing pathophysiologic disruption. Given these caveats, it is truly no wonder that the field has struggled to reach an adequate understanding. At this stage of our knowledge, it would be apt to say that the field is searching for a needle in the haystack. It is the hope of a number of investigators that the prize will be found somewhere at the interface of existing models of psychosis and more general theories and observations of ECT’s mechanism of action. In this review, we will compare and contrast the putative mechanisms of ECT and antipsychotic medications (a subset of the neurotransmitter theory) and also review alterations in neurotrophins and immune system modulations associated with ECT.
THE ANTIPSYCHOTIC EFFECTS OF ECT Psychosis is generally understood to comprise either or both of the frequently co-occurring disturbances of perception (hallucinations) and reality testing (delusions). Psychotic symptoms vary in their expression with regard to intensity and type and are frequently seen in conjunction with other positive symptoms of schizophrenia, such as thought and movement disorders (which are also very pertinent to the discussion of ECT’s overall benefits, but addressed more fully in other reviews within this special issue.) Nevertheless, psychosis is a marker of severe mental illness and its identification essential for diagnosis and treatment planning, which may well include ECT. Several observations of ECT response in psychotic states inform our mechanistic inquiry. It seems likely that the benefit of ECT in schizophrenia is not a specific “antischizophrenia” effect per se, but rather is a more general antipsychotic effect. This is illustrated by the fact that ECT has shown effectiveness in treating psychosis associated with a host of causes, despite their presumed divergent pathophysiologic mechanisms (Table 1). In this general sense, ECT mirrors the effectiveness of antipsychotic drugs, but ECT’s effectiveness in patients who are antipsychotic nonresponders suggests a different or more potent mechanism of action for some patients. Unfortunately, ECT is often relegated to treatment-refractory patients, and this may skew the findings in unpredictable ways. Furthermore, with the exception of schizophrenia, which often requires a protracted course of ECT and ultimately achieves a somewhat modest response, the reversal of psychosis in many ECT-responsive cases can be quite robust and occurs early in the course of treatment. For this reason, it may be appropriate to consider as pertinent to the mechanism of ECT those physiologic changes, which occur immediately after electroshock as well as those developing after repeated administration. In the case of mood disorders, the presence of psychotic symptoms is generally a positive predictor of ECT response,2 www.ectjournal.com
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TABLE 1. Electroconvulsive Therapy Responsive Psychotic States Disorders—Primary Psychiatric Major depressive disorder with psychotic features Schizophrenia Schizoaffective disorder Mania Psychosis due to general medical condition Parkinson disease Epilepsy Huntington disease Postpartum nonaffective psychosis Neuropsychiatric lupus and other autoimmune-associated psychoses Substance related PCP Psychostimulants Corticosteroids PCP indicates phencyclidine and other hallucinogens.
whereas patients will frequently show a marginal response to combined antidepressant plus antipsychotic medication.3 Of note, the psychotic symptoms associated with mood disorders are usually so thoroughly addressed by ECT that an antipsychotic drug is not necessarily required to keep psychotic symptoms at bay during the post-ECT continuation timeframe, whereas antidepressant administered concurrently during ECT administration amplifies response,4 and absent an antidepressant, patients are prone to early relapse.5 The demonstration of ECT’s effectiveness in reversing psychotic states induced by N-methyl-D-aspartate receptor antagonists such as phencyclidine and other hallucinogens6,7 and amphetamine8 points to a mechanism of action that spans the 2 primary pharmacologic models of psychosis. Again, this is also largely true for both typical and atypical antipsychotic medications, but the antipsychotic effect of ECT in Parkinson disease highlights a particular divergence. It is well known that late-stage Parkinson disease may be associated with both mood symptoms and psychotic symptoms, especially in the presence of dopamine (DA) agonists. The application of ECT in such circumstances will usually produce simultaneous improvement in both the motor symptoms and reductions in psychotic symptoms. Presumably, owing to the common pharmacologic mechanism of DA D2 receptor antagonism, antipsychotic medications (clozapine is a notable exception) risk worsening motor symptoms in patients with Parkinson with psychosis.9 Quetiapine has been shown in controlled trials to be free of motor adverse effects, but is ineffective in treating psychotic symptoms.10 However, ECT is not universally a single magic bullet for psychosis, as is seen in the studies of treatmentresistant schizophrenia, where ECT in combination with antipsychotic medication (particularly clozapine) is superior to either treatment in monotherapy.11–13 Therefore, it is safe to say that whereas the mechanism of ECT may overlap with antipsychotic drugs, it has unique properties that might further understanding of psychosis and the therapeutic benefit of the treatment.
COMPARISON WITH PHARMACOLOGIC EFFECTS OF ANTIPSYCHOTIC MEDICATIONS The earliest mechanistic understanding of antipsychotics proceeded from their ability to block DA receptors.14 The binding of antipsychotic drugs to the receptor prevents the postsynaptic
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effects of physiologic DA on G-proteins and opening of sodium ion channels. According to the DA model of psychosis as a state of aberrant salience, the dampening of DA neurotransmission by antipsychotics in mesocortical and mesolimbic pathways thereby diminishes chaotic and stimulus-independent release of DA, which is thought to cause context-inappropriate associations with random occurrences (delusions) and with internal representations of perceptions and memories (hallucinations).15 With the advent of the atypical antipsychotics, especially clozapine, the DA model has been expanded to include the ability to affect both DA and serotonin (5-HT) systems in the brain. Specifically, typical ADs are presumed to rely on DA D2/D3 receptor antagonism for antipsychotic potency, whereas the mechanism of action for atypical agents variably supplements DA antagonism with a more potent blockade of 5-HT2A, 2C, 6, and 7 receptors, plus partial agonism at 5-HT1A receptors.16 In the neurocircuitry of reward and emotion regulation, DA and 5-HT are anatomically and also functionally related, which means that a change in one system may affect the transmission of another. The role of serotonin receptors in the action of atypical antipsychotics is to hyperpolarize and inhibit neurons throughout the brain, including pyramidal glutamatergic neurons in the cerebral cortex and hippocampus, some GABAergic interneurons, ventral tegmental DA neurons, and 5HT neurons in the dorsal and median raphe.16 The blockade of 5HT-2A receptors by atypical antipsychotics differentially inhibits the simultaneous blockade of DA D2 receptors in the striatum, thereby diminishing extrapyramidal adverse effects, but there is also likely a direct or synergistic contribution of 5-HT binding on positive and negative symptoms as well as cognition in schizophrenia.16 Therefore, if ECT were to behave similarly to antipsychotic drugs, we would expect a net or appropriately localized (eg, mesolimbic) inhibition of DA D2–like activity and/or similarly inhibited or decreased 5-HT, with the exception of 5HT-1A receptor activity.
ELECTROCONVULSIVE THERAPY AND DOPAMINE There is evidence in both human (ECT) and animal (electroconvulsive shock [ECS]) studies pointing toward an overall activation of DA neurotransmission, which would be explanatory with regard to the effectiveness of ECT in diminishing motor symptoms of Parkinson disease and improving mood and motivation in MDD. However, in accordance with the DA hypothesis, a monolithic increase in DA would be expected to worsen or trigger psychosis in the manner of a DA agonist, such as amphetamine. This is certainly not characteristic of ECT. In a number of rodent models, ECS has been found to enhance the effect of DA agonists17,18 and to increase DA concentration and DA neuronal activity in a number of brain regions.19,20 Conversely, with repeated ECS, Chao et al21 demonstrated reversal of some but not all manifestations of abnormal behavior induced by chronic methamphetamine sensitization, a model of psychosis in mice. This finding illustrates how ECT may behave analogously with atypical antipsychotic agents with regard to differential effects across dopaminergically mediated neural networks. Both typical and atypical antipsychotic agents increase levels of homovanillic acid (HVA), a measure of DA turnover, in the cerebrospinal fluid, but it does not seem that this change is associated with treatment response in schizophrenia.22 After ECT, depressed patients have shown significantly increased cerebrospinal fluid (CSF) HVA, but small sample sizes and high proportion of responders prevent correlation with treatment response.23,24 Cooper et al25 assayed CSF monoamine metabolites at baseline, after the first treatment, and 1 day after 6 bitemporal © 2014 Lippincott Williams & Wilkins
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ECT treatments in 12 patients with schizophrenia. They found that concurrent with prominent reductions in positive symptoms, DA (but not noradrenaline nor serotonin) metabolites were found to be elevated. However, the increase in the CSF concentration of HVA that was seen after the first treatment returned to pretreatment levels by the end of 6 treatments. The authors hypothesize that the increase in DA turnover might represent a decrease in postsynaptic DA receptor density ultimately resulting in improvement of psychosis. However, in a sample of Asian patients, 14 patients with depression and 10 patients with schizophrenia, a more recent study found no change in urinary DA levels after the first and final ECT, or 1 week after a flexibly dosed course of bitemporal ECT.26 Studies of receptor density or regional DA activity during or after ECT in humans are currently lacking but might go a long way toward elucidating the role of this neurotransmitter in ECT’s mechanism of action.
ELECTROCONVULSIVE THERAPY AND SEROTONIN In rodents receiving repeated ECS, an enhancement of serotonin neurotransmission is one of the most consistent effects, associated with increased 5-hydroxy-idolacetic-acid (5-HIAA) metabolites, up-regulation of the 5-HT receptor, and an increase in known 5-HT–mediated behaviors.27 The effect of ECT on serotonin in humans is less certain but seems to be in the opposite direction, which would be more consistent with effects of atypical antipsychotic. Early studies of the serotonergic effects of antipsychotic medications and ECT on patients with schizophrenia examined the serotonin metabolite 5-HIAA in serum and CSF. Cerebrospinal fluid HIAA is elevated in association with treatment with chlorpromazine,28 but not with olanzapine22 or ECT.28,29 Three studies have examined 5-HT binding in depressed patients. Yatham et al30 used the positron emission tomography radiotracer [18F]setoperone, which preferentially binds to 5HT2A receptors in a study of 15 patients who underwent titrated right unilateral ECT at 3 times threshold. They showed a 5-HT downregulation in all cortical regions, with peak changes in the parahippocampal gyrus and media prefrontal cortex. Two studies examined the effect of 5-HT1A binding using positron emission tomography [11C]WAY 100635 scans. One study showed no change,31 whereas the other found widespread reductions after ECT, with strongest reductions in subgenual anterior cingulate cortex, orbitofrontal cortex, amygdala, hippocampus, and amygdala.32 Whereas no studies have examined 5HT or DA binding specifically in psychotic disorders, the demonstration by McCormick et al of a significant correlation between the degree of decreased left subgenual anterior cingulate cortex metabolism and percentage of change in positive symptom scores might suggest a productive line of inquiry.33 The existing evidence regarding the effects of ECT on DA and 5-HT are limited and also possibly confounded by differences across diagnosis and species. However, it seems that consistent with its broad spectrum of physiologic effects, ECT has effects on these neurotransmitters that bear some overall similarities to the atypical antipsychotic agents, which might prove useful in the consideration of further research efforts.
NEUROTROPHIC EFFECTS OF ANTIPSYCHOTICS AND ECT The neurodevelopmental hypothesis suggests that impairments in neurodevelopmental processes as a result of genetic and/or environmental insults lead to the development of schizophrenia.34 Neurotrophins like brain-derived neurotrophic factor © 2014 Lippincott Williams & Wilkins
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(BDNF) play a key role in neuronal survival, differentiation, maintenance, and connectivity of nerve cells during development as well as adulthood.35 Moreover, substantial evidence suggests that neurotrophins are involved in stress response and function of hypothalamic-pituitary-adrenocortical axis response.36 Accordingly, many studies have investigated BDNF levels in the brain as well as peripheral samples of subjects with schizophrenia. Although the data from these studies report mixed results, there is a strong evidence for decrease in BDNF levels in serum/plasma of schizophrenia subjects.37 Furthermore, atypical and typical antipsychotics have been shown to induce differential effects on neurotrophins such as BDNF and nerve growth factor in clinical and preclinical studies with atypical agents less liable to induce deleterious effects.37,38 In preclinical models, ECS induces the levels of neuroprotective molecules like BDNF, erythropoietin, and vascular endothelial growth factor (VEGF) in brain regions involved in cognition and memory.39 Electroconvulsive shock is known to induce the proliferation of hippocampal progenitor cells,40 and it promotes the maturation of dendritic spines and increases spine density.41 Several reports are available on the neurotrophic effects of ECT in clinical populations and peripheral BDNF levels. A case study reported significant increase in serum BDNF levels in a severe treatment-resistant schizophrenia subject during the course of ECT.42 However, the study by Fernandes et al43 did not find any significant difference in serum BDNF levels after ECT in patients with refractory schizophrenia, although ECT was associated with symptom improvement. Although data on the effects of ECT on neurotrophins in schizophrenia are limited, a number of studies have investigated the role of BDNF in depressed subjects before and after ECT treatment. Electroconvulsive therapy has been shown to increase serum BDNF levels in drug-resistant depressed subjects.44 In another study, the increase in serum BDNF levels after ECT was found to be significantly correlated with the decrease in total 17-item Hamilton Rating Scale for Depression score and cluster scores of cognitive dysfunction and retardation in depressed subjects.45 However, a few other studies did not find any significant change in serum BDNF levels after ECT in depressed subjects.46,47 The discrepancy in the data on BDNF levels might be due to age, differences in the sample population, stage of illness, methodology, sex and subtype, and medication history. Therefore, more detailed studies with larger sample sizes are warranted before making any conclusions on the role of BDNF in mediating ECT-induced antipsychotic effects in patients with schizophrenia. It is known that BDNF mediates its neurotrophic actions by increasing the activities of antioxidant enzymes.48 Oxidative stress has been implicated in the pathophysiological process of schizophrenia, with increased levels of lipid peroxides reported in subjects with schizophrenia.49,50 A recent study has reported improvements in clinical symptoms with reductions in serum malondialdehyde, a marker for lipid peroxidation, compared to the baseline after ECT session in patients with schizophrenia.51 Therefore, future studies should explore the balance between oxidative stress and neuroprotection as a key measure to understand the therapeutic potential of ECT in schizophrenia.
AUTOIMMUNITY AND INFLAMMATION IN THE PATHOPHYSIOLOGY OF PSYCHOSIS A pathophysiological role for inflammatory abnormalities in psychosis has been an enduring finding in the field, albeit with heterogeneous results, including negative studies. Recently, increased understanding of the complex interactions between inflammation and the brain in other chronic diseases has better www.ectjournal.com
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informed this relationship in psychosis. Several lines of evidence support an association between immune system dysfunction and psychosis. Risk factors for schizophrenia include immunerelated genes,52 prenatal maternal infections,53 autoimmune disorders,54 and hospitalization for infections.55 Blood levels of cytokines,56 C-reactive protein (CRP),57 and lymphocytes58 and the prevalence of blood autoantibodies against multiple antigens59 are abnormal/elevated in patients with schizophrenia. Patients with acute psychosis also have increased CSF macrophages60,61 and interleukin-662,63 as well as evidence of microglial activation.64 A subset of patients presenting with acute psychosis has autoantibodies associated with limbic encephalitis (most commonly anti–N-methyl-D-aspartate receptor antibodies) in the absence of overt signs of neurologic disease.59 There is also evidence from randomized controlled trials that adjunctive treatment with nonsteroidal anti-inflammatory drugs may improve the psychotic symptoms in some patients with schizophrenia.65 However, the potential pathophysiologic mechanism(s) by which immune dysfunction might mediate psychosis remains unclear. Inflammatory molecules (eg, cytokines) and autoantibodies can cross the blood-brain barrier but, alternatively, can also be synthesized de novo in the central nervous system. It has been proposed that abnormal allostasis (eg, psychosocial stress, infection or immune disorder, or tissue injury) results in cellular activation and proinflammatory cytokine production, as well as stimulation of an acute phase response. In the setting of increased blood-brain barrier permeability, autoantibodies may directly cross-react with central nervous system antigens, or cytokines may directly modulate dopaminergic neurotransmission or indirectly modulate glutamatergic neurotransmission through tryptophan catabolism, thereby contributing to psychosis.66
PUTATIVE ANTIPSYCHOTIC EFFECTS OF ECT: IMMUNE SYSTEM MODULATION Despite evidence for an association between immune system dysfunction and psychosis in some patients, relatively few studies have investigated the impact of ECT on the immune system. Furthermore, many of studies considered only acute effects (minutes to hours after treatment) of ECT on immune parameters in patients with nonpsychotic major depression, and are limited by small sample size and unreplicated findings. Nonetheless, given meta-analytic evidence for increased inflammation, as measured by blood cytokine levels, in schizophrenia,56 bipolar disorder,67 and major depressive disorder (MDD),68 and the potential effectiveness of anti-inflammatory therapies in these disorders,69,70 further investigation of immune-mediated antipsychotic effects of ECT is warranted. We briefly summarize existing findings on immune effects of ECT and suggest next steps in this area. Fluitman et al71 studied acute immune effects (up to 30 minutes after ECT) in 12 patients with depression, including 4 patients with MDD with psychotic features. They found that acute ECT significantly altered stimulated production of interleukin (IL)-6, tumor necrosis factor α (TNF-α), interferon-gamma (IFN-γ), and also briefly increased natural killer cell activity, but that repeated ECT did not have a significant effect on any of these parameters. Chaturvedi et al72 investigated acute hematologic effects (up to 2 hours after ECT) in 31 patients, of whom 17 had schizophrenia or a related psychotic disorder. They found a significant increase in white blood cell and differential neutrophil counts, and decrease in absolute lymphocyte counts. There are 2 case reports of successful treatment of psychotic depression related to interferon treatment for hepatitis C.73,74 McCormick
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et al33 found in 10 patients with psychotic depression, that the decrease in positive symptoms after ECT was correlated with increased left hippocampal metabolism. Ohaeri et al75 performed unmodified ECT (ie, no anesthesia) in 8 subjects with acute functional psychoses, six of who had measurable blood CRP levels, in Nigeria. Interestingly, CRP fell significantly to undetectable levels after the sixth ECT treatment in 5 of these 6 subjects, and decreased by almost 50% in the sixth subject. Outside of psychosis, acute immune effects of ECT include alterations in levels of IL-1β, IL-6, natural killer cell activity, total lymphocytes, and lymphocyte subsets.76–80 Lehtimaki et al80 also found that IL-6 release correlated to the stimulus dose used, suggesting neuronal depolarization as a mechanism of cytokine release. Another study did not find any change over 3 days in blood CRP levels after ECT.81 After a series of ECT sessions, changes in absolute and differential lymphocytes as well as lymphocyte proliferative responses have also been reported.76,77 Three other studies found relationships between longitudinal immune effects of ECT and effects on depression. Hestad et al82 found significantly higher TNF-α levels in 23 depressed patients than in 15 age- and sex-matched controls. Among the 15 depressed patients who received ECT, clinical improvement was accompanied by a gradual, significant decrease in TNF-α (to levels comparable to controls). By contrast, there was no change in TNF-α levels in the 8 depressed patients followed longitudinally without ECT. In a study of 15 patients with major depression, Rotter et al83 found that change in TNF-β, IL-5, and bone morphogenetic protein 6 over the course of ECT were significantly correlated with depression scale scores. Several studies have also found that increases in levels of neurotrophins, including VEGF and BDNF, over the course of ECT were significantly correlated with improvements in depression scores.84–86 It is important to note that IL-1β, IL-6, TNF-α, lymphocyte, VEGF, and BDNF levels all may be abnormal in psychosis.56,58,87,88 There is evidence in both schizophrenia and bipolar disorder that blood levels of some cytokines, important regulators of inflammation, and lymphocytes may be clinical state-related markers,56,58,67 that is, patients have higher concentrations of some cytokines than controls during periods of symptom exacerbation, but there is no difference during periods of clinical stability. Consistent with these findings, there is evidence that response to ECT may be correlated with changes in immune parameters, including CRP and TNF-α, which are abnormal in schizophrenia and mood disorders. Future studies in larger samples should measure longitudinal changes in multiple parameters, including CRP, IL-1β, IL-6, TNF-α, lymphocytes, BDNF, VEGF, and psychotic symptoms, before and after ECT, and explore whether baseline levels of any of these parameters predict response to treatment. These findings could provide clues regarding potential mechanisms of antipsychotic effects of ECT.
SUMMARY AND CONCLUSIONS Our review is limited by the dearth of studies that focus on the effect of ECT on psychosis specifically and on ECT mechanisms in general. A number of confounding factors hamper conclusions, including the problems associated with extrapolating from animal models to human conditions and the assumption that psychosis may be compared across diagnostic categories. Other confounding factors specific to the human literature include small sample sizes, lack of replicated findings, absence of sham ECT conditions, and the difficulty controlling for the neurophysiologic effects of concomitant medications. © 2014 Lippincott Williams & Wilkins
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As an encouragement to investigators, the successful elucidation of the mechanism underpinning ECT’s rapid and complete reversal of the positive symptoms of psychosis in a broad range of conditions may be seen as a genuine holy grail for the field. Certainly, this review illustrates that the literature investigating the antipsychotic effects of ECT lags behind that of mood disorders. With regard to neurotransmitter and neurotrophic effects, however, limited data suggest ECT shares some similar properties with atypical antipsychotic medications. The possibility that ECT might also modulate the immune system and thereby influence the course of psychotic disorders is intriguing but at this time remains speculative. REFERENCES 1. Leiknes KA, Jarosh-von SL, Hoie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012;2:283–344. 2. Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17:244–253. 3. Wijkstra J, Lijmer J, Balk FJ, et al. Pharmacological treatment for unipolar psychotic depression: systematic review and meta-analysis. Br J Psychiatry. 2006;188:410–415. 4. Haskett RF, Rosenquist PB, McCall WV, et al. The role of antidepressant medications during ECT: new findings from OPT-ECT. J ECT. 2007;23:56. 5. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285:1299–1307. 6. Dinwiddie SH, Drevets WC, Smith DR. Treatment of phencyclidine-associated psychosis with ECT. Convuls Ther. 1988;4:230–235. 7. Rosen AM, Mukherjee S, Shinbach K. The efficacy of ECT in phencyclidine-induced psychosis. J Clin Psychiatry. 1984;45:220–222. 8. Grelotti DJ, Kanayama G, Pope HG Jr. Remission of persistent methamphetamine-induced psychosis after electroconvulsive therapy: presentation of a case and review of the literature. Am J Psychiatry. 2010;167:17–23. 9. Friedman JH. Parkinson disease psychosis: update. Behav Neurol. 2013;27:469–477. 10. Rabey JM, Prokhorov T, Miniovitz A, et al. Effect of quetiapine in psychotic Parkinson’s disease patients: a double-blind labeled study of 3 months’ duration. Mov Disord. 2007;22:313–318. 11. Chanpattana W, Chakrabhand ML, Kongsakon R, et al. Short-term effect of combined ECT and neuroleptic therapy in treatment-resistant schizophrenia. J ECT. 1999;15:129–139. 12. Braga RJ, Petrides G. The combined use of electroconvulsive therapy and antipsychotics in patients with schizophrenia. J ECT. 2005;21:75–83. 13. Masoudzadeh A, Khalilian AR. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J Biol Sci. 2007;10:4287–4290. 14. Carlsson A. Antipsychotic drugs, neurotransmitters, and schizophrenia. Am J Psychiatry. 1978;135:165–173.
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55. Benros ME, Nielsen PR, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011; 168:1303–1310.
38. Pillai A, Terry AV Jr, Mahadik SP. Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res. 2006;82:95–106. 39. Newton SS, Collier EF, Hunsberger J, et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci. 2003;23:10841–10851. 40. Madsen TM, Treschow A, Bengzon J, et al. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry. 2000;47:1043–1049. 41. Zhao C, Warner-Schmidt J, Duman RS, et al. Electroconvulsive seizure promotes spine maturation in newborn dentate granule cells in adult rat. Dev Neurobiol. 2012;72:937–942. 42. Martinotti G, Ricci V, Di Nicola M, et al. Brain-derived neurotrophic factor and electroconvulsive therapy in a schizophrenic patient with treatment-resistant paranoid-hallucinatory symptoms. J ECT. 2011;27:e44–e46. 43. Fernandes BS, Massuda R, Torres M, et al. Improvement of schizophrenia with electroconvulsive therapy and serum brain-derived neurotrophic factor levels: lack of association in a pilot study. Psychiatry Clin Neurosci. 2010;64:663–665. 44. Bocchio-Chiavetto L, Zanardini R, et al. Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients. Eur Neuropsychopharmacol. 2006;16:620–624. 45. Hu Y, Yu X, Yang F, et al. The level of serum brain-derived neurotrophic factor is associated with the therapeutic efficacy of modified electroconvulsive therapy in Chinese patients with depression. J ECT. 2010;26:121–125. 46. Grønli O, Stensland GØ, Wynn R, et al. Neurotrophic factors in serum following ECT: a pilot study. World J Biol Psychiatry. 2009;10:295–301. 47. Fernandes B, Gama CS, Massuda R, et al. Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients. Neurosci Lett. 2009;453:195–198. 48. Skaper SD, Floreani M, Negro A, et al. Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J Neurochem. 1998;70:1859–1868. 49. Mahadik SP, Pillai A, Joshi S, et al. Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. Int Rev Psychiatry. 2006;18:119–131. 50. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress inschizophrenia. Biol Psychiatry. 2013; 74:400–409. 51. Kartalci S, Karabulut AB, Ozcan AC, et al. Acute and chronic effects of electroconvulsive treatment on oxidative parameters in schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1689–1694. 52. Hsu PC, Nwulia E, Sawa A. Using bioinformatic tools. Am J Psychiatry. 2009;166:854. International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–752.
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56. Miller B, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663–671. 57. Miller BJ, Culpepper N, Rapaport MH. C-Reactive Protein in Schizophrenia: A Review and Meta-Analysis. Clin Schizophr Relat Psychoses. 2014;7:223–230. 58. Miller B, Gassama B, Sebastian D, et al. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73:993–999. 59. Ezeoke A, Mellor A, Buckley P, et al. A systematic quantitative review of blood autoantibody elevations in schizophrenia. Schizophr Res. 2013;150:245–251. 60. Nikkilä H, Müller K, Ahokas A, et al. Abnormal distributions of T-lymphocyte subsets in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res. 1995;14:215–221. 61. Nikkilä HV, Müller K, Ahokas A, et al. Accumulation of macrophages in the CSF of schizophrenic patients. Am J Psychiatry. 1999;156: 1725–1729. 62. Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacol. 2003;28:1515–1520. 63. Sasayama D, Hattori K, Wakabayashi C, et al. Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder. J Psychiatr Res. 2013;47:401–406. 64. Doorduin J, de Vries EF, Willemsen AT, et al. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009;50:1801–1807. 65. Nitta M, Kishimoto T, Müller N, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230–1241. 66. Miller BJ, Buckley P. Is relapse in schizophrenia an immune-mediated effect? FOCUS: The Journal of Lifelong Learning in Psychiatry. 2012;10:115–123. 67. Modabbernia A, Taslimi S, Brietzke E, et al. Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry. 2013;74:15–25. 68. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–457. 69. Fond G, Hamdani N, Kapczinski F, et al. Effectiveness and tolerance of anti-inflammatory drugs’ add-on therapy in major mental disorders: a systematic qualitative review. Acta Psychiatr Scand. 2013; Nov 11. doi: 10.1111/acps.12211. 70. Sommer IE, van Westrhenen R, Begemann MJ, et al. Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophr Bull. 2014;40:181–191. 71. Fluitman SB, Heijnen CJ, Denys DA, et al. Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder. J Affect Disord. 2011;131:388–392. 72. Chaturvedi S, Chadda RK, Rusia U, et al. Effect of electroconvulsive therapy on hematological parameters. Psychiatry Res. 2001;102: 265–268.
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73. Prior T, Chue P. Psychotic depression occurring after stopping interferon-alpha. J Clin Psychopharmacol. 1999;19:385–386. 74. Zincke MT, Kurani A, Istafanous R, et al. The successful use of electroconvulsive therapy in a patient with interferon-induced psychotic depression. J ECT. 2007;23:291–292. 75. Ohaeri JU, Hedo CC, Lagundoye OO. The profile of C-reactive proteins in functional psychotic states in a cohort in Nigeria. Acta Psychiatr Scand. 1993;88:252–255. 76. Albrecht J, Helderman JH, Schlesser MA, et al. A controlled study of cellular immune function in affective disorders before and during somatic therapy. Psychiatry Res. 1985;15:185–193. 77. Fischler B, Bocken R, Schneider I, et al. Immune changes induced by electroconvulsive therapy (ECT). Ann N Y Acad Sci. 1992;650:326–330. 78. Kronfol Z, Nair MP, Weinberg V, et al. Acute effects of electroconvulsive therapy on lymphocyte natural killer cell activity in patients with major depression. J Affect Disord. 2002;71:211–215.
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82. Hestad KA, Tønseth S, Støen CD, et al. Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J ECT. 2003;19:183–188. 83. Rotter A, Biermann T, Stark C, et al. Changes of cytokine profiles during electroconvulsive therapy in patients with major depression. J ECT. 2013;29:162–169. 84. Bocchio-Chiavetto L, Zanardini R, Bortolomasi M, et al. Electroconvulsive Therapy (ECT) increases serum Brain Derived Neurotrophic Factor (BDNF) in drug resistant depressed patients. Eur Neuropsychopharmacol. 2006;16:620–624. 85. Minelli A, Zanardini R, Abate M, et al. Vascular Endothelial Growth Factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1322–1325.
79. Kronfol Z, Lemay L, Nair M, et al. Electroconvulsive therapy increases plasma levels of interleukin-6. Ann NY Acad Sci. 594, 463–465.
86. Piccinni A, Del Debbio A, Medda P, et al. Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving electroconvulsive therapy. Eur Neuropsychopharmacol. 2009;19:349–355.
80. Lehtimäki K, Keränen T, Huuhka M, et al. Increase in plasma proinflammatory cytokines after electroconvulsive therapy in patients with depressive disorder. J ECT. 2008;24:88–91.
87. Di Nicola M, Cattaneo A, Hepgul N, et al. Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun. 2013;31:90–95.
81. Giltay EJ, Kho KH, Blansjaar BA. Serum markers of brain-cell damage and C-reactive protein are unaffected by electroconvulsive therapy. World J Biol Psychiatry. 2008;9:231–235.
88. Green MJ, Matheson SL, Shepherd A, et al. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry. 2011;16:960–972.
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The Antipsychotic Effects of ECT A Review of Possible Mechanisms
Peter B. Rosenquist, MD, Brian Miller, MD, MPH, PhD, and Anilkumar Pillai, PhD Objectives: Electroconvulsive therapy (ECT) exhibits demonstrable effectiveness for psychotic symptoms associated with a broad range of neuropsychiatric conditions. However, the mechanism remains poorly understood particularly with regard to antipsychotic effects. Methods: We examined studies of ECT in schizophrenia and mood disorders, as well as from animal models of psychotic disorders, and compared the results to those of antipsychotic medications. This review focuses on 3 potential domains of exploration of ECT’s antipsychotic effects: dopamine and serotonin neurotransmitter activity, neurotrophic effects, and immune system modulation. Results: Preliminary results support a putative role for all three of these domains but are limited by a lack of replicated findings, including negative studies. Conclusions: A comparison of the neurophysiologic and molecular properties of antipsychotic drugs and ECT reveals some overlap, but there are also distinctive differences; and the significance of these findings remains uncertain. Key Words: ECT, antipsychotic drugs, mechanism of action, cytokines, brain-derived neurotrophic factor (J ECT 2014;30: 125–131)
S
ince the inception of ECT, patients and practitioners have wondered, “How does it work?” Despite keen interest, the mechanisms of action underpinning the remarkable and broad therapeutic effectiveness remain poorly understood. In this regard, very little inquiry has focused specifically on the antipsychotic effects of ECT, perhaps mirroring clinical practice in the treatment of schizophrenia as the archetypal psychotic disorder. For most of the Western hemisphere, ECT is largely considered a treatment for major depression and bipolar disorder and is rarely used to treat schizophrenia, its use having declined since the 1960s with the advent of effective antipsychotic medication.1 However, in Eastern nations such as India, China, parts of Africa, and other developing countries, ECT is viewed as a first-line treatment of severe psychosis when symptoms require hospitalization. Similarly, in the case of the secondary psychoses associated with other neuropsychiatric conditions and drug-induced states, ECT is used second line for treatment-resistant cases. The literature for these conditions is therefore limited to smaller studies, case reports, and case series, which serves to hinder systematic inquiry into mechanisms of action. Nevertheless, ECT has demonstrable antipsychotic effects, which can be observed across a number of conditions, most notably in mood disorders with accompanying psychotic features, and is being reconsidered as a viable option in treatment-resistant schizophrenia.
From the Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, Augusta, GA Received for publication February 18, 2014; accepted March 11, 2014. Reprints: Peter B. Rosenquist, MD, Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, 997 St Sebastian Way, Augusta, GA 30912 (e‐mail: [email protected]). The authors have no conflicts of interest or financial disclosures to report. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/YCT.0000000000000131
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Consistent with its broad spectrum of efficacy, we assume for the purposes of this review that ECT induces widespread and multidimensional neurophysiologic changes within the brain. Additional axioms are that the pathophysiologic state influences, and is influenced by, ECT. Therefore, ECTs demonstrated effects in nonpsychotic states may or may not be applicable to psychotic states. Finally, it is presumed that only a subset of the many ECT-induced changes in brain function, structure produce clinical improvement, and are as likely to be compensatory as directly responsible for reversing pathophysiologic disruption. Given these caveats, it is truly no wonder that the field has struggled to reach an adequate understanding. At this stage of our knowledge, it would be apt to say that the field is searching for a needle in the haystack. It is the hope of a number of investigators that the prize will be found somewhere at the interface of existing models of psychosis and more general theories and observations of ECT’s mechanism of action. In this review, we will compare and contrast the putative mechanisms of ECT and antipsychotic medications (a subset of the neurotransmitter theory) and also review alterations in neurotrophins and immune system modulations associated with ECT.
THE ANTIPSYCHOTIC EFFECTS OF ECT Psychosis is generally understood to comprise either or both of the frequently co-occurring disturbances of perception (hallucinations) and reality testing (delusions). Psychotic symptoms vary in their expression with regard to intensity and type and are frequently seen in conjunction with other positive symptoms of schizophrenia, such as thought and movement disorders (which are also very pertinent to the discussion of ECT’s overall benefits, but addressed more fully in other reviews within this special issue.) Nevertheless, psychosis is a marker of severe mental illness and its identification essential for diagnosis and treatment planning, which may well include ECT. Several observations of ECT response in psychotic states inform our mechanistic inquiry. It seems likely that the benefit of ECT in schizophrenia is not a specific “antischizophrenia” effect per se, but rather is a more general antipsychotic effect. This is illustrated by the fact that ECT has shown effectiveness in treating psychosis associated with a host of causes, despite their presumed divergent pathophysiologic mechanisms (Table 1). In this general sense, ECT mirrors the effectiveness of antipsychotic drugs, but ECT’s effectiveness in patients who are antipsychotic nonresponders suggests a different or more potent mechanism of action for some patients. Unfortunately, ECT is often relegated to treatment-refractory patients, and this may skew the findings in unpredictable ways. Furthermore, with the exception of schizophrenia, which often requires a protracted course of ECT and ultimately achieves a somewhat modest response, the reversal of psychosis in many ECT-responsive cases can be quite robust and occurs early in the course of treatment. For this reason, it may be appropriate to consider as pertinent to the mechanism of ECT those physiologic changes, which occur immediately after electroshock as well as those developing after repeated administration. In the case of mood disorders, the presence of psychotic symptoms is generally a positive predictor of ECT response,2 www.ectjournal.com
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TABLE 1. Electroconvulsive Therapy Responsive Psychotic States Disorders—Primary Psychiatric Major depressive disorder with psychotic features Schizophrenia Schizoaffective disorder Mania Psychosis due to general medical condition Parkinson disease Epilepsy Huntington disease Postpartum nonaffective psychosis Neuropsychiatric lupus and other autoimmune-associated psychoses Substance related PCP Psychostimulants Corticosteroids PCP indicates phencyclidine and other hallucinogens.
whereas patients will frequently show a marginal response to combined antidepressant plus antipsychotic medication.3 Of note, the psychotic symptoms associated with mood disorders are usually so thoroughly addressed by ECT that an antipsychotic drug is not necessarily required to keep psychotic symptoms at bay during the post-ECT continuation timeframe, whereas antidepressant administered concurrently during ECT administration amplifies response,4 and absent an antidepressant, patients are prone to early relapse.5 The demonstration of ECT’s effectiveness in reversing psychotic states induced by N-methyl-D-aspartate receptor antagonists such as phencyclidine and other hallucinogens6,7 and amphetamine8 points to a mechanism of action that spans the 2 primary pharmacologic models of psychosis. Again, this is also largely true for both typical and atypical antipsychotic medications, but the antipsychotic effect of ECT in Parkinson disease highlights a particular divergence. It is well known that late-stage Parkinson disease may be associated with both mood symptoms and psychotic symptoms, especially in the presence of dopamine (DA) agonists. The application of ECT in such circumstances will usually produce simultaneous improvement in both the motor symptoms and reductions in psychotic symptoms. Presumably, owing to the common pharmacologic mechanism of DA D2 receptor antagonism, antipsychotic medications (clozapine is a notable exception) risk worsening motor symptoms in patients with Parkinson with psychosis.9 Quetiapine has been shown in controlled trials to be free of motor adverse effects, but is ineffective in treating psychotic symptoms.10 However, ECT is not universally a single magic bullet for psychosis, as is seen in the studies of treatmentresistant schizophrenia, where ECT in combination with antipsychotic medication (particularly clozapine) is superior to either treatment in monotherapy.11–13 Therefore, it is safe to say that whereas the mechanism of ECT may overlap with antipsychotic drugs, it has unique properties that might further understanding of psychosis and the therapeutic benefit of the treatment.
COMPARISON WITH PHARMACOLOGIC EFFECTS OF ANTIPSYCHOTIC MEDICATIONS The earliest mechanistic understanding of antipsychotics proceeded from their ability to block DA receptors.14 The binding of antipsychotic drugs to the receptor prevents the postsynaptic
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effects of physiologic DA on G-proteins and opening of sodium ion channels. According to the DA model of psychosis as a state of aberrant salience, the dampening of DA neurotransmission by antipsychotics in mesocortical and mesolimbic pathways thereby diminishes chaotic and stimulus-independent release of DA, which is thought to cause context-inappropriate associations with random occurrences (delusions) and with internal representations of perceptions and memories (hallucinations).15 With the advent of the atypical antipsychotics, especially clozapine, the DA model has been expanded to include the ability to affect both DA and serotonin (5-HT) systems in the brain. Specifically, typical ADs are presumed to rely on DA D2/D3 receptor antagonism for antipsychotic potency, whereas the mechanism of action for atypical agents variably supplements DA antagonism with a more potent blockade of 5-HT2A, 2C, 6, and 7 receptors, plus partial agonism at 5-HT1A receptors.16 In the neurocircuitry of reward and emotion regulation, DA and 5-HT are anatomically and also functionally related, which means that a change in one system may affect the transmission of another. The role of serotonin receptors in the action of atypical antipsychotics is to hyperpolarize and inhibit neurons throughout the brain, including pyramidal glutamatergic neurons in the cerebral cortex and hippocampus, some GABAergic interneurons, ventral tegmental DA neurons, and 5HT neurons in the dorsal and median raphe.16 The blockade of 5HT-2A receptors by atypical antipsychotics differentially inhibits the simultaneous blockade of DA D2 receptors in the striatum, thereby diminishing extrapyramidal adverse effects, but there is also likely a direct or synergistic contribution of 5-HT binding on positive and negative symptoms as well as cognition in schizophrenia.16 Therefore, if ECT were to behave similarly to antipsychotic drugs, we would expect a net or appropriately localized (eg, mesolimbic) inhibition of DA D2–like activity and/or similarly inhibited or decreased 5-HT, with the exception of 5HT-1A receptor activity.
ELECTROCONVULSIVE THERAPY AND DOPAMINE There is evidence in both human (ECT) and animal (electroconvulsive shock [ECS]) studies pointing toward an overall activation of DA neurotransmission, which would be explanatory with regard to the effectiveness of ECT in diminishing motor symptoms of Parkinson disease and improving mood and motivation in MDD. However, in accordance with the DA hypothesis, a monolithic increase in DA would be expected to worsen or trigger psychosis in the manner of a DA agonist, such as amphetamine. This is certainly not characteristic of ECT. In a number of rodent models, ECS has been found to enhance the effect of DA agonists17,18 and to increase DA concentration and DA neuronal activity in a number of brain regions.19,20 Conversely, with repeated ECS, Chao et al21 demonstrated reversal of some but not all manifestations of abnormal behavior induced by chronic methamphetamine sensitization, a model of psychosis in mice. This finding illustrates how ECT may behave analogously with atypical antipsychotic agents with regard to differential effects across dopaminergically mediated neural networks. Both typical and atypical antipsychotic agents increase levels of homovanillic acid (HVA), a measure of DA turnover, in the cerebrospinal fluid, but it does not seem that this change is associated with treatment response in schizophrenia.22 After ECT, depressed patients have shown significantly increased cerebrospinal fluid (CSF) HVA, but small sample sizes and high proportion of responders prevent correlation with treatment response.23,24 Cooper et al25 assayed CSF monoamine metabolites at baseline, after the first treatment, and 1 day after 6 bitemporal © 2014 Lippincott Williams & Wilkins
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ECT treatments in 12 patients with schizophrenia. They found that concurrent with prominent reductions in positive symptoms, DA (but not noradrenaline nor serotonin) metabolites were found to be elevated. However, the increase in the CSF concentration of HVA that was seen after the first treatment returned to pretreatment levels by the end of 6 treatments. The authors hypothesize that the increase in DA turnover might represent a decrease in postsynaptic DA receptor density ultimately resulting in improvement of psychosis. However, in a sample of Asian patients, 14 patients with depression and 10 patients with schizophrenia, a more recent study found no change in urinary DA levels after the first and final ECT, or 1 week after a flexibly dosed course of bitemporal ECT.26 Studies of receptor density or regional DA activity during or after ECT in humans are currently lacking but might go a long way toward elucidating the role of this neurotransmitter in ECT’s mechanism of action.
ELECTROCONVULSIVE THERAPY AND SEROTONIN In rodents receiving repeated ECS, an enhancement of serotonin neurotransmission is one of the most consistent effects, associated with increased 5-hydroxy-idolacetic-acid (5-HIAA) metabolites, up-regulation of the 5-HT receptor, and an increase in known 5-HT–mediated behaviors.27 The effect of ECT on serotonin in humans is less certain but seems to be in the opposite direction, which would be more consistent with effects of atypical antipsychotic. Early studies of the serotonergic effects of antipsychotic medications and ECT on patients with schizophrenia examined the serotonin metabolite 5-HIAA in serum and CSF. Cerebrospinal fluid HIAA is elevated in association with treatment with chlorpromazine,28 but not with olanzapine22 or ECT.28,29 Three studies have examined 5-HT binding in depressed patients. Yatham et al30 used the positron emission tomography radiotracer [18F]setoperone, which preferentially binds to 5HT2A receptors in a study of 15 patients who underwent titrated right unilateral ECT at 3 times threshold. They showed a 5-HT downregulation in all cortical regions, with peak changes in the parahippocampal gyrus and media prefrontal cortex. Two studies examined the effect of 5-HT1A binding using positron emission tomography [11C]WAY 100635 scans. One study showed no change,31 whereas the other found widespread reductions after ECT, with strongest reductions in subgenual anterior cingulate cortex, orbitofrontal cortex, amygdala, hippocampus, and amygdala.32 Whereas no studies have examined 5HT or DA binding specifically in psychotic disorders, the demonstration by McCormick et al of a significant correlation between the degree of decreased left subgenual anterior cingulate cortex metabolism and percentage of change in positive symptom scores might suggest a productive line of inquiry.33 The existing evidence regarding the effects of ECT on DA and 5-HT are limited and also possibly confounded by differences across diagnosis and species. However, it seems that consistent with its broad spectrum of physiologic effects, ECT has effects on these neurotransmitters that bear some overall similarities to the atypical antipsychotic agents, which might prove useful in the consideration of further research efforts.
NEUROTROPHIC EFFECTS OF ANTIPSYCHOTICS AND ECT The neurodevelopmental hypothesis suggests that impairments in neurodevelopmental processes as a result of genetic and/or environmental insults lead to the development of schizophrenia.34 Neurotrophins like brain-derived neurotrophic factor © 2014 Lippincott Williams & Wilkins
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(BDNF) play a key role in neuronal survival, differentiation, maintenance, and connectivity of nerve cells during development as well as adulthood.35 Moreover, substantial evidence suggests that neurotrophins are involved in stress response and function of hypothalamic-pituitary-adrenocortical axis response.36 Accordingly, many studies have investigated BDNF levels in the brain as well as peripheral samples of subjects with schizophrenia. Although the data from these studies report mixed results, there is a strong evidence for decrease in BDNF levels in serum/plasma of schizophrenia subjects.37 Furthermore, atypical and typical antipsychotics have been shown to induce differential effects on neurotrophins such as BDNF and nerve growth factor in clinical and preclinical studies with atypical agents less liable to induce deleterious effects.37,38 In preclinical models, ECS induces the levels of neuroprotective molecules like BDNF, erythropoietin, and vascular endothelial growth factor (VEGF) in brain regions involved in cognition and memory.39 Electroconvulsive shock is known to induce the proliferation of hippocampal progenitor cells,40 and it promotes the maturation of dendritic spines and increases spine density.41 Several reports are available on the neurotrophic effects of ECT in clinical populations and peripheral BDNF levels. A case study reported significant increase in serum BDNF levels in a severe treatment-resistant schizophrenia subject during the course of ECT.42 However, the study by Fernandes et al43 did not find any significant difference in serum BDNF levels after ECT in patients with refractory schizophrenia, although ECT was associated with symptom improvement. Although data on the effects of ECT on neurotrophins in schizophrenia are limited, a number of studies have investigated the role of BDNF in depressed subjects before and after ECT treatment. Electroconvulsive therapy has been shown to increase serum BDNF levels in drug-resistant depressed subjects.44 In another study, the increase in serum BDNF levels after ECT was found to be significantly correlated with the decrease in total 17-item Hamilton Rating Scale for Depression score and cluster scores of cognitive dysfunction and retardation in depressed subjects.45 However, a few other studies did not find any significant change in serum BDNF levels after ECT in depressed subjects.46,47 The discrepancy in the data on BDNF levels might be due to age, differences in the sample population, stage of illness, methodology, sex and subtype, and medication history. Therefore, more detailed studies with larger sample sizes are warranted before making any conclusions on the role of BDNF in mediating ECT-induced antipsychotic effects in patients with schizophrenia. It is known that BDNF mediates its neurotrophic actions by increasing the activities of antioxidant enzymes.48 Oxidative stress has been implicated in the pathophysiological process of schizophrenia, with increased levels of lipid peroxides reported in subjects with schizophrenia.49,50 A recent study has reported improvements in clinical symptoms with reductions in serum malondialdehyde, a marker for lipid peroxidation, compared to the baseline after ECT session in patients with schizophrenia.51 Therefore, future studies should explore the balance between oxidative stress and neuroprotection as a key measure to understand the therapeutic potential of ECT in schizophrenia.
AUTOIMMUNITY AND INFLAMMATION IN THE PATHOPHYSIOLOGY OF PSYCHOSIS A pathophysiological role for inflammatory abnormalities in psychosis has been an enduring finding in the field, albeit with heterogeneous results, including negative studies. Recently, increased understanding of the complex interactions between inflammation and the brain in other chronic diseases has better www.ectjournal.com
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informed this relationship in psychosis. Several lines of evidence support an association between immune system dysfunction and psychosis. Risk factors for schizophrenia include immunerelated genes,52 prenatal maternal infections,53 autoimmune disorders,54 and hospitalization for infections.55 Blood levels of cytokines,56 C-reactive protein (CRP),57 and lymphocytes58 and the prevalence of blood autoantibodies against multiple antigens59 are abnormal/elevated in patients with schizophrenia. Patients with acute psychosis also have increased CSF macrophages60,61 and interleukin-662,63 as well as evidence of microglial activation.64 A subset of patients presenting with acute psychosis has autoantibodies associated with limbic encephalitis (most commonly anti–N-methyl-D-aspartate receptor antibodies) in the absence of overt signs of neurologic disease.59 There is also evidence from randomized controlled trials that adjunctive treatment with nonsteroidal anti-inflammatory drugs may improve the psychotic symptoms in some patients with schizophrenia.65 However, the potential pathophysiologic mechanism(s) by which immune dysfunction might mediate psychosis remains unclear. Inflammatory molecules (eg, cytokines) and autoantibodies can cross the blood-brain barrier but, alternatively, can also be synthesized de novo in the central nervous system. It has been proposed that abnormal allostasis (eg, psychosocial stress, infection or immune disorder, or tissue injury) results in cellular activation and proinflammatory cytokine production, as well as stimulation of an acute phase response. In the setting of increased blood-brain barrier permeability, autoantibodies may directly cross-react with central nervous system antigens, or cytokines may directly modulate dopaminergic neurotransmission or indirectly modulate glutamatergic neurotransmission through tryptophan catabolism, thereby contributing to psychosis.66
PUTATIVE ANTIPSYCHOTIC EFFECTS OF ECT: IMMUNE SYSTEM MODULATION Despite evidence for an association between immune system dysfunction and psychosis in some patients, relatively few studies have investigated the impact of ECT on the immune system. Furthermore, many of studies considered only acute effects (minutes to hours after treatment) of ECT on immune parameters in patients with nonpsychotic major depression, and are limited by small sample size and unreplicated findings. Nonetheless, given meta-analytic evidence for increased inflammation, as measured by blood cytokine levels, in schizophrenia,56 bipolar disorder,67 and major depressive disorder (MDD),68 and the potential effectiveness of anti-inflammatory therapies in these disorders,69,70 further investigation of immune-mediated antipsychotic effects of ECT is warranted. We briefly summarize existing findings on immune effects of ECT and suggest next steps in this area. Fluitman et al71 studied acute immune effects (up to 30 minutes after ECT) in 12 patients with depression, including 4 patients with MDD with psychotic features. They found that acute ECT significantly altered stimulated production of interleukin (IL)-6, tumor necrosis factor α (TNF-α), interferon-gamma (IFN-γ), and also briefly increased natural killer cell activity, but that repeated ECT did not have a significant effect on any of these parameters. Chaturvedi et al72 investigated acute hematologic effects (up to 2 hours after ECT) in 31 patients, of whom 17 had schizophrenia or a related psychotic disorder. They found a significant increase in white blood cell and differential neutrophil counts, and decrease in absolute lymphocyte counts. There are 2 case reports of successful treatment of psychotic depression related to interferon treatment for hepatitis C.73,74 McCormick
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et al33 found in 10 patients with psychotic depression, that the decrease in positive symptoms after ECT was correlated with increased left hippocampal metabolism. Ohaeri et al75 performed unmodified ECT (ie, no anesthesia) in 8 subjects with acute functional psychoses, six of who had measurable blood CRP levels, in Nigeria. Interestingly, CRP fell significantly to undetectable levels after the sixth ECT treatment in 5 of these 6 subjects, and decreased by almost 50% in the sixth subject. Outside of psychosis, acute immune effects of ECT include alterations in levels of IL-1β, IL-6, natural killer cell activity, total lymphocytes, and lymphocyte subsets.76–80 Lehtimaki et al80 also found that IL-6 release correlated to the stimulus dose used, suggesting neuronal depolarization as a mechanism of cytokine release. Another study did not find any change over 3 days in blood CRP levels after ECT.81 After a series of ECT sessions, changes in absolute and differential lymphocytes as well as lymphocyte proliferative responses have also been reported.76,77 Three other studies found relationships between longitudinal immune effects of ECT and effects on depression. Hestad et al82 found significantly higher TNF-α levels in 23 depressed patients than in 15 age- and sex-matched controls. Among the 15 depressed patients who received ECT, clinical improvement was accompanied by a gradual, significant decrease in TNF-α (to levels comparable to controls). By contrast, there was no change in TNF-α levels in the 8 depressed patients followed longitudinally without ECT. In a study of 15 patients with major depression, Rotter et al83 found that change in TNF-β, IL-5, and bone morphogenetic protein 6 over the course of ECT were significantly correlated with depression scale scores. Several studies have also found that increases in levels of neurotrophins, including VEGF and BDNF, over the course of ECT were significantly correlated with improvements in depression scores.84–86 It is important to note that IL-1β, IL-6, TNF-α, lymphocyte, VEGF, and BDNF levels all may be abnormal in psychosis.56,58,87,88 There is evidence in both schizophrenia and bipolar disorder that blood levels of some cytokines, important regulators of inflammation, and lymphocytes may be clinical state-related markers,56,58,67 that is, patients have higher concentrations of some cytokines than controls during periods of symptom exacerbation, but there is no difference during periods of clinical stability. Consistent with these findings, there is evidence that response to ECT may be correlated with changes in immune parameters, including CRP and TNF-α, which are abnormal in schizophrenia and mood disorders. Future studies in larger samples should measure longitudinal changes in multiple parameters, including CRP, IL-1β, IL-6, TNF-α, lymphocytes, BDNF, VEGF, and psychotic symptoms, before and after ECT, and explore whether baseline levels of any of these parameters predict response to treatment. These findings could provide clues regarding potential mechanisms of antipsychotic effects of ECT.
SUMMARY AND CONCLUSIONS Our review is limited by the dearth of studies that focus on the effect of ECT on psychosis specifically and on ECT mechanisms in general. A number of confounding factors hamper conclusions, including the problems associated with extrapolating from animal models to human conditions and the assumption that psychosis may be compared across diagnostic categories. Other confounding factors specific to the human literature include small sample sizes, lack of replicated findings, absence of sham ECT conditions, and the difficulty controlling for the neurophysiologic effects of concomitant medications. © 2014 Lippincott Williams & Wilkins
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As an encouragement to investigators, the successful elucidation of the mechanism underpinning ECT’s rapid and complete reversal of the positive symptoms of psychosis in a broad range of conditions may be seen as a genuine holy grail for the field. Certainly, this review illustrates that the literature investigating the antipsychotic effects of ECT lags behind that of mood disorders. With regard to neurotransmitter and neurotrophic effects, however, limited data suggest ECT shares some similar properties with atypical antipsychotic medications. The possibility that ECT might also modulate the immune system and thereby influence the course of psychotic disorders is intriguing but at this time remains speculative. REFERENCES 1. Leiknes KA, Jarosh-von SL, Hoie B. Contemporary use and practice of electroconvulsive therapy worldwide. Brain Behav. 2012;2:283–344. 2. Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17:244–253. 3. Wijkstra J, Lijmer J, Balk FJ, et al. Pharmacological treatment for unipolar psychotic depression: systematic review and meta-analysis. Br J Psychiatry. 2006;188:410–415. 4. Haskett RF, Rosenquist PB, McCall WV, et al. The role of antidepressant medications during ECT: new findings from OPT-ECT. J ECT. 2007;23:56. 5. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. 2001;285:1299–1307. 6. Dinwiddie SH, Drevets WC, Smith DR. Treatment of phencyclidine-associated psychosis with ECT. Convuls Ther. 1988;4:230–235. 7. Rosen AM, Mukherjee S, Shinbach K. The efficacy of ECT in phencyclidine-induced psychosis. J Clin Psychiatry. 1984;45:220–222. 8. Grelotti DJ, Kanayama G, Pope HG Jr. Remission of persistent methamphetamine-induced psychosis after electroconvulsive therapy: presentation of a case and review of the literature. Am J Psychiatry. 2010;167:17–23. 9. Friedman JH. Parkinson disease psychosis: update. Behav Neurol. 2013;27:469–477. 10. Rabey JM, Prokhorov T, Miniovitz A, et al. Effect of quetiapine in psychotic Parkinson’s disease patients: a double-blind labeled study of 3 months’ duration. Mov Disord. 2007;22:313–318. 11. Chanpattana W, Chakrabhand ML, Kongsakon R, et al. Short-term effect of combined ECT and neuroleptic therapy in treatment-resistant schizophrenia. J ECT. 1999;15:129–139. 12. Braga RJ, Petrides G. The combined use of electroconvulsive therapy and antipsychotics in patients with schizophrenia. J ECT. 2005;21:75–83. 13. Masoudzadeh A, Khalilian AR. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J Biol Sci. 2007;10:4287–4290. 14. Carlsson A. Antipsychotic drugs, neurotransmitters, and schizophrenia. Am J Psychiatry. 1978;135:165–173.
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