- Psychological Issues
The classic model of mental illness in the first half of the 20th century held that stress was the cause of psychiatric illness in an otherwise healthy person (Gershon, 1990, p. 369). In more recent years, we have found biological clues that point to the true root of these mental illnesses.
Insofar as unipolar depression and bipolar disorder (affective disorders) are concerned, as Cicchetti and Toth (1995, p. 409) state, “There is growing consensus that there are multiple pathways to depression. Moreover, not all depressed or manic-depressive individual experience each potential biological or psychological dysfunction that is examined.” To this end, I will examine the multiple theories that have been advanced, and the biological states that occur, as possible views into the causes for unipolar depression and bipolar disorder, with the view that one of these theories may be right, or that two or more of these theories may be right, and act in concert in the same person or separately in different people.
There exists incontrovertible evidence that both unipolar depression and bipolar disorder are genetically linked. However, unlike the color of our eyes or hair, which is based solely upon simple Mendelian genetics, it appears that unipolar and bipolar are expressed as a tendency rather than a simple mathematical model (Cicchetti & Toth, 1995, p. 400).
Many studies have been done to examine the issue of environment versus genes. They found that in monozygotic (MZ), or identical, twins, there was a concordance rate of 54 – 65% for unipolar depression, with the concordance rate even higher in bipolar disorder, at 79%. There was only a concordance rate of 14 – 19% percent in dizygotic (DZ) or fraternal, twins in both cases. This clearly shows a genetic link for both unipolar and bipolar disorders (Frude, 1998, p. 124; Gershon, 1990, p. 377).
Additionally, there is evidence of a cross-link between bipolar and unipolar disorders, as of the 32 MZ twins who were positively concordant for an affective illness, 11 were unipolar, 14 were bipolar, and 7 had one twin unipolar and the other bipolar (Gershon, 1990, p. 377).
Unipolar depression also appears frequently among relatives of those with bipolar disorder, although bipolar disorder does not occur more frequently than normal among family members of those diagnosed with unipolar depression (Feldman, Meyer, & Quenzer, 1997, p. 821).
Gershon (1990, p. 378) further gives evidence against a purely “nurture” Hypothesis for affective disorders through a review of literature regarding adoptees. Of adoptees with affective disorders, their adoptive parents had an affective disorder only 12 percent of the time, while the biological parents manifested an affective disorder 29%.
The dysregulation model of depression, as proposed by Siever and Davis (1985), suggests that depression is due to inappropriate (i.e. less selective) environmental responsiveness, and defective habituation (i.e. a slower return to baseline functioning following a perturbation). They believe that this is due to a chronic abnormality with the pattern and degree of responsiveness of a neurotransmitter.
Through learned helplessness, first suggested by Seligman in 1975, animals which are exposed to a major stressor (usually an electric shock, or being forced to swim to exhaustion) are subsequently unable to learn to escape that stressor (Willner, 1994, p. 297). This has correlation with the affective disorders, as it was shown that short term treatment (3-7 days) with anti-depressants would reverse the effects, and allow the animals to again be able to learn to “escape” the shock. It is hypothesized that either dopamine or norepinephrine functions are being altered in susceptible individuals. (Willner, 1994, p. 297-298).
According to Feldman, Meyer, and Quenzer (1997, p. 823) and Janicak, Davis, Preskorn, and Ayd (1993, p.217), in their reviews of literature, there is sufficient evidence to support the possibility of a desynchronization of biological rhythms as a possible culprit in the affective disorders. This includes: decreased total sleep time, increase sleep onset latency, decreased sleep arousal threshold, increased wakefulness, more frequent changes between sleep stages, and terminal insomnia. Additionally, there is rapid eye movement (REM) sleep effects also associated with affective disorders, including: a decrease in REM onset latency, an increase in REM density, and a redistribution of REM sleep to earlier in the sleep cycle. The abnormalities in sleep patterns are similar to those of a person who has been required to alter their sleep pattern by 12 hours.
The effectiveness of phototherapy in seasonal affective depression (SAD) also is supportive of the theory of a desynchronization of circadian rhythms.
When behavior become more severe and occurs more rapidly in response to the same dose of a given psychomotor stimulant, behavioral sensitization is said to have occurred. It is believed to involve dopamine at some point in the process, and can be modified by other neurochemicals such as sex hormones and vasopressin (Goodwin & Jamison, 1990, p.406)
In kindling, as in behavioral sensitization, there is an increased response to the same level and duration of stimulation. This can be either a response to a previously unresponded to stimuli, or an increase in response to an already responded to stimuli. (Goodwin & Jamison, 1990, p. 406; Swann, 1993, p. 20).
While these last two theories do not explain affective disorders directly, they do show parallels with bipolar disorder, according to Goodwin and Jamison (1990, p. 406): that thresholds can be altered; early episodes require a higher level of a precipitant than do later episodes; and that the young are ore vulnerable to sensitization and kindling which is similar to the relatively early age onset of bipolar disorder.
With the theories sensitization and kindling, it is possible to see that those afflicted with bipolar disorder would succumb to spontaneous episodes with no precipitant stress, which is in fact what can occur. Thus, early and vigorous treatment of episodes is mandatory to prevent the changes associated with sensitization and kindling from occurring (Goodwin & Jamison, 1990, p. 407).
If this is true, each episode of an affective illness may leave behind a residue that has the potential to change the neurobiological functioning of the brain, and to potentially alter what medications may be effective.
The first three models examined, on the other hand show how biological changes can affect the mood, and thus either biologically cause the onset of an affective disorder, or exacerbate an already existing disorder.
The amine neurotransmitter system has been widely studied as a cause of affective disorders. The cell bodies are mostly concentrated within the limbic system, but each can synapse with thousands of other nerve cells throughout the brain.
The general tenet of the catecholemine Hypothesis is that a functional deficit of catecholamines in the neurotransmitter synapses causes depression, while an excess causes mania. Of these norepinephrine and dopamine are the most widely studies.
Norepinephrine serves to act as a modulator of other signals within the brain, rather than serving as a primary signal transmitter itself (Goodwin & Jamison, 1990, p. 418). 85 – 90% of central nervous system norepinephrine stores are in approximately 5000 neurons in the locus coeruleus, with projections spread throughout the brain to the hippocampus, cerebral cortex, amygdala, and lower brain stem (Janicak, Davis, Preskorn, & Ayd, 1993, p. 211). Norepinephrine is seen to be elevated in the manic state versus a normal or depressed state, in direct relation to the severity of the mania (Swann, 1993). The effects of norepinephrine are best described in terms of the receptors it interacts with: the alpha1- alpha2- and beta-adrenergic receptors. It is these receptors that undergo the most change with treatment. These receptors interface with the norepinephrine to manufacture cAMP, a second-messenger (Brown, Steinberg & van Praag, 1994, p.335-336).
Dopamine is most widely associated with alterations in movement disorders such as Parkinsons disease (Goodwin & Jamison, 1990, p. 418), along with reinforcing, motivational, and psychomotor processes. As with norepinephrine, dopamine appears to be higher during manic than depressed states (Swann, 1993, p. 3-4). There have been some pharmacological studies which indicate dopamine plays a role in bipolar illness: L-dopa (a dopamine precursor) can induce hypomania in bipolar patients; Amphetamine, which produces a dopamine release and inhibits uptake of dopamine can cause hypomania in bipolar patients and a hypomanic like state in normal patients, yet does not function as an anti-depressant in unipolar depressed patients; and, neuroleptics which selectively block dopamine receptors are effective against mania (Fibiger, 1996, p. 2; Goodwin & Jamison, 1990, p. 420). There have been a number of theories raised regarding dopamine and affective disorders (Brown, Steinberg & van Praag, 1994, p.328):
The indolamine serotonin, much like norepinephrine, plays a modulatory role in the central nervous system. Most serotonin is located within relatively few pathways, with the midbrain raphe nuclei to limbic hippocampal/amygdala path being the most important (Janicak, Davis, Preskorn, & Ayd, 1993, p.213). As opposed to norepinephrine though, there have been no correlations between cerebral spinal fluid levels of serotonin and either manic or depressed states (although depressive effects can occur when serotonin depleting agents are administered). While the levels of serotonin may be normal, there is the possibility that there is a functional deficit, as shown through post-mortem studies and neuroendocrine challenges of both unipolar and bipolar patients (Swann, 1993, p. 4). After treatment with antidepressants, depressed individuals will show increased serotonin receptor sensitivity, neurotransmission and function (Brown, Steinberg & van Praag, 1994, p.318-324).
According to Swann (1993, p. 6), the main support for the possibility of acetylcholine as a factor in affective disorders is that drugs that increase acetylcholine have the potential to induce mania or alleviate depression. There is little direct evidence of support. What evidence there is comes from the fact that administration of cholinergic agonists produces symptoms similar to those of depression (Andreasen & Black, 1995, p.278).
Gamma-Aminobutyric Acid (GABA)
GABA is the major inhibitory neurotransmitter in the brain (Goodwin & Jamison, 1990, p. 424), and diminishes the activity of its target neurons. The cornerstone to the GABA Hypothesis of bipolar disorder is that it provides inhibitory actions to both norepinephrine and dopamine systems. As such, if there is a deficiency of GABA, especially within the limbic structures, a manic state may result (Goodwin & Jamison, 1990, p. 425).
As noted by Goodwin and Jamison (1990, p. 445) “The central nervous system can be likened unto a net. If you pull any single mesh in the met, the shape of every other mesh will change”, which very aptly describes the relationship of the neurotransmitters in the brain. Rather than a single neurotransmitter being involved in the affective disorders, it appears that several may be important. The ratios of multiple neurotransmitters to one another may play a larger role than the actual amount present of any one single neurotransmitter.
The neuroendocrine Hypotheses are seen as secondary to other pathology – that occurring within the neurotransmitters. The hormones within the neuroendocrine system are largely secreted in response to neurotransmitters, and thus, while they may exact a primary effect in the affective disorders, they must be viewed as being “downstream” from the root cause of the problem.
Elevated cortisol has been consistently seen in depressed patients for decades, over many different studies (Goodwin & Jamison, 1990, p. 448). Gerner and Wilkins (1983) also suggest that cortisol is decreased during the manic phase of bipolar disorder. There is ample evidence that the cortisol levels can be directly related to one of the earlier neurotransmitter theories. Cortisol, in the adrenal gland, is released in response to ACTH from the pituitary, which is released in response to corticotropin-releasing factor (CRF) in the hypothalamus. The CRF release is mediated positively by acetylcholine, serotonin, and norepinephrine, and negatively by GABA (Pepper & Krieger, 1984).
Thyroid function has long been associated with a change in mood (Prange, Wilson, Lara, & Alltop, 1974) – in fact, before a diagnosis of depression is made, often a thyroid panel is run. Up to 20% of depressed patient have bee found to have anti-thyroid antibodies in a number of studies (Gold, Pottash, & Extein, 1982; Nemeroff, Simon, Haggerty, & Evans, 1985), while others lack the normal peak secretion of Thyroid Stimulating Hormone (TSH) that occurs during the night (Goodwin & Jamison, 1990, p. 454; Swann, 1993, p. 8). Additionally, Bauer and Whybrow (1988) make a comprehensive review of studies which examine serum T3 and T4, which are stimulated to be released by TSH, and have direct effect on the central nervous system. Their conclusion is that the effects of circulating T3 ant T4 in affective disorders is unclear, but there is too much data to rule them out as possible effectors. Goodwin and Jamison (1990, p. 455) also note that production of TSH in response to thyrotropin-releasing hormone (TRH) can vary within the same person depending if they are in a manic or depressed state, if bipolar. Just as noted for Cortisol, the end hormones T3 and T4 are ultimately controlled by a neurotransmitter, in this case, norepinephrine, which has a positive effect on TRH in the hypothalamus.
Growth hormone is normally increased when sleep begins. However, with persons with depression, the increase can be minimal or missing (Goodwin & Jamison, 1990, p. 455). They suggest that this could be due to a decreased sensitivity to hypothalamic dopamine receptors. Growth Hormone is again dependent upon a neurotransmitter for release, in that it is positively affected by dopamine and norepinephrine.
Prolactin is inhibited by Dopamine, but is also influenced by a number of other factors, not the least of which is the menstrual cycle in women. Depue, Arbisi, Spoont, Krauss, Leon, and Ainsworth (1989) discovered lower levels of prolactin in depressed patients during the summer and winter periods, in patients with seasonal affective disorder.
Melatonin production over a 24 hour period has been shown to be significantly higher in manic than depressed patients according to Lewy, Wher, Goodwin, Newsome, and Markey (1980). Melatonin production is in the pineal gland, and like many other neurohormones, is stimulated by norepinephrine.
The neuroendocrine system cannot itself be the root biological cause of the affective disorders – the endocrine system must be modulated by other systems. However, the view cannot just be taken that the neuroendocrine system is a way to look at those other systems from the bottom up. While the neurotransmitter systems modulate the neuroendocrine systems, they have much different effects. The neuroendocrine hormones, which may circulate for hours in the central nervous system, have much longer lasting effects than the neurotransmitters, which are active in a synaptic cleft for less than a second. The two systems must be looked at together in order to gain a fuller understanding of the possible causes of these disorders.
A large part of the active substances in the central nervous system are neuropeptides, and they have been found in the areas of the brain regulating emotion. There are a number of these which showed altered levels in depressed or manic patients.
Somatostatin has an inhibitory effect on the hypothalamic-pituitary-adrenal (HPA) axis. With depression, Somatostatin showed decreased levels in 5 of 6 studies (Goodwin & Jamison, 1990 p. 462), but no change in the manic state. This would serve to disinhibit the HPA-axis even further than as noted previously.
Vasopressin is involved in maintaining the circadian rhythms, and sleep among other functions. Gjerris, Hammer, Vendsborg, Christensen, and Rafaelsen (1985) demonstrated that depressed patients had significantly lower levels of vasopressin than manic patients, which bracketed normals to the low and high respectively.
Goodwin and Jamison (1990, p. 464) report that oxytocin has the opposite effect of vasopressin: it can cause amnesia vs. enhancing learning. They also report opposite biological results, in that manics have lower levels of oxytocin relative to those with depression.
Neuropeptides are similar to the neuroendocrine system in that they produce longer lasting effects than do neurotransmitters. However, unlike the neuroendocrine system, they are not wholly reliant on neurotransmitters to be activated, and may provide an alternate, or synergistic pathway from which to view the biology of affective disorders.
When measured with Positron Emission Tomography (PET), glucose metabolism was reported to be lower in the depressed and higher in the manic patient, on a diffuse scale (Swann, 1993, p. 16).
On a similar note, what has been termed “subcortical encephalomalacia” has been consistently seen in mood disorder patients in MRI studies (Sackeim & Prohovnik, 1993, p. 224-225). These are scattered hyperintensities on the MRI scans of unknown origin.
In a review of studies done on asymmetrical brain functioning, Cicchetti and Toth (1993, p. 406-407) found that decreased left hemisphere activation often results in increased symptoms of depression. They felt this was not in and of itself sufficient to cause depression, but merely to exacerbate the symptoms or predispose the person to an affective disorder.
There are a wide range of medications, even a wide range of classifications which are utilized to treat affective disorders. These range from a simple salt to antidepressants to anticonvulsants to antipsychotics. Even these classifications are not heterogeneous. The fact is that we have medications to treat each possible root system, to treat the symptoms, and where one fails, another is waiting in the wings.
Monamine Oxidase Inhibitors
The monamine oxidase inhibitors (MAOIs) work by the inhibition of monamine oxidase, which degrades the monamines, including norepinephrine, serotonin, and dopamine. Through this action, they increase the available monamines available within the CNS (Nolen, 1997, p. 385-386).
The tricyclic antidepressants (TCAs) are the simplest of the common antidepressants, and work by the inhibition of the reuptake of monamines norepinephrine and serotonin (Hale, 1997, p. 365). They do not decrease the uptake of the amines into the storage granuales, but only from the extra neuronal space into the axon terminals (Feldman, Meyer, & Quenzer, 1997, p. 833).
Selective Serotonin Reuptake Inhibitors
The selective serotonin reuptake inhibitors (SSRIs) act to selectively block the reuptake of only serotonin, and only affect other monamines in a minimal way. In general, they provide approximately 70% inhibition of serotonin reuptake (Hale, 1997, p. 368). While Antidepressants have been known to historically have the possibility of making bipolar patients manic, Peet (1994) says that this is a lowered risk with the SSRIs as compared to tricyclic antidepressants.
Lithium is generally considered a mood stabilizer for bipolar disorder. However, as Katona and Robertson (1997, p. 416) review, controlled trials have shown lithium to have antidepressant effects at least equivalent to that of the TCAs. They also note however, that it is generally not used alone, but in combination with another antidepressant in refractory depression.
The action of lithium is not clear, but it is known to act to facilitate the release of serotonin, and increase the activity of postsynaptic norepinephrine and serotonin receptors, and dopamine receptors (Feldman, Meyer, Quenzer, 1997, p.852-858; Kashani, & Nair, 1996, p. 250). Through its interactions with the electrolyte systems, it also alters intracellular calcium levels, much as do the calcium channel blockers as noted below.
Anticonvulsants in mood disorders have four major effects: the increasing of the seizure threshold; decreasing the seizure duration; decreasing the neurometabolic response to an episode; and decreasing the phenomena of amygdaloid kindling (Janicak, Davis, Preskorn, & Ayd, 1993, p. 296). Essentially, they make it more difficult for the postsynaptic neuron to reach its excitation threshold either electrically or neurochemically, and once it has been reached, decreases the widespread effects.
antipsychotic medications are utilized in conjunction with antidepressants, or mood stabilizers when psychotic symptoms are present, or to enhance the effect of other medications when attempting to control mania (Guttmacher, 1994, p. 29). Almost all antipsychotic medications act to block the receptor for dopamine (Janicak, Davis, Preskorn, & Ayd, 1993, p. 94).
anxiolytic medications are utilized with affective disorders in a number of ways. The first is as a sleep medication, secondly to decrease anxiety and agitation, and lastly as an antidepressant (Van Megen, Van Vliet, Westenberg, & Den Boer, 1997, p.427-428). They note that the antidepressant effects, with certain anxiolytics, namely Alprazolam, was statistically significant, and equivalent to tricyclic antidepressants in a number of cases.
The anxiolytics act by binding to the a receptor site that recognizes both GABA-a and benzodiazepines, which allows a chloride ion into the cell, changing the intracellular environment (Guttmacher, 1994, p.159).
Calcium Channel Blockers
Calcium Channel Blockers, while historically antihypertensive medications, are utilized as mood stabilizers. They act to decrease calcium channel activity, which diminishes intracellular Calcium (Janicak, Davis, Preskorn, & Ayd, 1993, p. 345). Through this activity, they affect the calcium dependent release of neurotransmitters in presynaptic neurons.
The fact that there is such a wide range of medications available for the affective disorders, and that they act is such diverse ways points to a very interconnected etiology of depression. Where one medication acts on one system, it eventually will have effects on other systems peripherally. The antidepressants have in common the fact that they all work by the inhibition of the reuptake or breakdown of the neurotransmitters – but not necessarily the same ones. As suggested earlier, if you pull on one part of the net, you will pull on all parts. This all serves to change the excitation of the neurons. There are also have more direct methods of affecting the excitation through the anticonvulsants and calcium channel blockers.
In short, the affective disorders are one of the mental disorders that have the widest array of medication classes available to them, and they can be used in a polypharmacy modality to achieve increased effectiveness.
Electroconvulsive Therapy (ECT) has moved into the modern ages, with safety concerns, and no pain, in fact no awareness to the patient. However, such movies as “One Flew Over the Cuckoo’s Nest” have played ECT into a very bad light in the thoughts of most of society today. Other than the admitted sequela of confusion, and occasional memory lapses, ECT is a painless procedure that is performed while the patient is under general anesthesia. In fact, today, according to Guttmacher (1994, p. 128), in patients surveyed one year after having ECT, only 18% stated it was worse than going to the dentist.
ECT in its simplest form is the inducing of a seizure within the patient. The major decision being faced is whether a patient is to receive unilateral or bilateral ECT. Bilateral ECT, in which electrodes are placed over both hemispheres of the brain, results in greater sequela, but faster response to ECT, and a lesser number of treatments (up to 50%) has classically been shown (Abrams, 1997, p. 138). In Unilateral ECT, the electrodes are placed over the right hemisphere, to avoid the language areas. The result is “marked diminution and, at times, absence of confusion associated with electric shock therapy” (Abrams, 1997, p. 137). However, with Increased levels of stimulation, it is believed that unilateral stimulation can be as effective as bilateral in more recent studies (Wiferatne, Halliday, & Lyn, 1999).
ECT has shown great efficacy, higher than that of many of our best medications (Guttmacher, 1994, p. 122):
|ECT||Comparison Tx||Percent (%)|
|ECT vs. Sham ECT||73||36||33||63||31%|
|ECT vs Placebo||138||22||69||86||41%|
|ECT vs HCA*||169||26||152||25||20%|
|ECT vs MAOI**||140||24||63||99||45%|
|*HCA – Heterocyclic Antidepressant|
**MAOI – Monamine Oxidase Inhibitor
When compared with newer antidepressants, such as Paroxetine, (an SSRI), ECT was still found to be superior, and patients had a faster response rate than any antidepressant (Wiferatne, Halliday, & Lyn, 1999).
Additionally, ECT has been associated with shorter hospital stays for acute depression, lower mortality over three year periods, and fewer suicide attempts at six-month follow-ups (Guttmacher, 1994, p. 123; Wiferatne, Halliday, & Lyn, 1999).
ECT has been found to be useful in mania as well as depression, but is generally used as a second line treatment. Unilateral ECT does not work in mania, so bilateral ECT must be utilized. The efficacy is similar to that of lithium, but is also often effective in pharmacotherapy resistant patients (Guttmacher, 1994, p. 123; Wiferatne, Halliday, & Lyn, 1999).
During ECT, an electrical stimulus is applied, in an attempt to depolarize a sufficient number of neurons to instigate a generalized cerebral seizure. With continued ECT, the patient will have “abnormal” EEG recordings for a substantial length of time (in excess of a year) after the last treatment (Abrams, 1997, p. 64)
One relationship between improvement with ECT and EEG recordings is increased slowing of brain waves as shown by increased frontal delta activity. In addition, ECT appears to cause a decrease in prefrontal cerebral blood flow lasting for over a week. When taken together, these two factors appear to be the strongest physiological basis for the workings of ECT (Abrams, 1997, p. 67-71).
It is suggested that ECT may also work by the inhibition of kindling, especially in the amygdala (Guttmacher, 1994, p. 143). With each successive ECT treatment, a higher electrical stimulus is required to cause the generalized seizure. Thus, acting like anticonvulsant medications, ECT makes the activation potential for the post-synaptic neurons higher.
Chronic ECT increases the serotonin receptors for both norepinephrin and serotonin receptors 5-HT2, while decreasing the receptors 5-HT1a. This accounts for the antidepressant affect, while also possibly accounting for part of the disorientation and restlessness, and disorientation that accompanies ECT (Feldman, Meyer, & Quenzer, 1997, p. 853).
Intracellularly, the levels of Ca drop, possibly decreasing the potential firing of the presynaptic vesical., at the time when antidepressant effects are beginning to be seen.
During ECT, there are a number of hormonal changes which occur as well. Affected hormones include prolactin, thyrotropin, cortisol, oxytocin and vasopressin. Many others including testosterone, lutenizing hormone, endorphins, prostaglandin and ACTH have also been identified as being impacted by ECT.
The changes in prolactin levels are the most widely studied neurochemical effects of ECT, as there is a 10 to 50 fold increase in serum levels immediately postictal (Abrams, 1997, p. 256). However, in a comprehensive review of studies cited by Abrams (1997, p. 256), no correlation was found between significant improvement in patients and increased prolactin levels.
Thyrotropin (thyroid stimulating hormone) is also acutely released from the posterior pituitary during ECT, often in correlation with prolactin (Cooper, Finlayson, Velamoor, Magnus, Cernovsky, 1989). No correlation, again, has been found, between anti-depressant effects and thyrotropin levels (Abrams, 1997, p. 260). It is possible, however, that in patients with low thyroid levels, an increase in thyrotropin could conceivably raise their mood state, if this had not been previously treated medically.
Cortisol levels have historically been known to be elevated in the blood of persons who are depressed. This is due to the stress, it is hypothesized. With ECT, the cortisol levels immediately following the treatment will rise (Weizman, Gil-Ad, Grupper, Tyano, Laron, 1987), and then begin to fall as the person begins to rise out of the depression. There is no evidence that the ECT directly causes the fall in the cortisol. It is believed to be a function of the decreased depressive state instead.
Oxytocin and Vasopressin
Oxytocin and vasopressin both have 10-fold increases in plasma concentrations at 5 minutes post ECT (Smith, Williams, Burkett, Glue, Nutt, 1990). These appear to mediate the release of cortisol, although, again, no direct impact on patient outcome has been detected.
King and Liston (1990) sum up the current state of knowledge regarding the biochemical effects of ECT:
Taken together, however, the myriad biochemical sequela of electroconvulsive stimulation, the gaps in our knowledge of their functional correlates, and the difficulties in extrapolation from animal to man or from normal to pathophysiological states makes it tenuous to entrust the therapeutic efficacy of ECT to the observable change in specific transmitter, receptor, or system.
There are many Hypotheses and sequela that have been brought forward, and, as noted, no one single path will likely be right. Unfortunately, due to the relative inaccessibility of the human brain, we have to content ourselves with measuring metabolites of primary neurochemical we are wishing to study, or other indirect methods. We have a wide range of treatments available which can alter one or many of these neurochemicals, as is needed, selectively, and we continue to devise new methods of measuring and testing, to learn more about the inner self.
One of the Hypothesis modifications learned through the judicious use of pharmacology is that rather than a specific neurotransmitter being the culprit in affective disorders, is that since we can achieve the same results through the modification of virtually any of the monoamines, possibly the receptor sites are where the problem lies. This is supported by the fact that antidepressants chemically affect the neurotransmitters within hours of their ingestion, yet require weeks to take effect. If a modification is actually taking place within the neuronal body in response to the levels of monamines, the time frame would seem more appropriate.
This does not take into account the quicker action of ECT, versus many of the standard pharmacologic medications. The other explanation would be that ECT, despite all of the neurochemical effects it exerts, affects the kindling of the receptor cells on a short term basis (with the length of time in direct relation to the number of ECT’s administered, and if ECT’s are given in an ongoing maintenance mode), which decreases the ability of the neurochemicals to cause activity within the brain structure. Essentially, the ECT acts in an immediate inhibitory manner.