At first glance, movement, mood, and obsessive-compulsive disorders seem a strange assortment of conditions to group together, but there is commonality in the anatomical and neurochemical findings and treatment of these disparate conditions. Symptoms coexist in varying combinations diseases such as depression, obsessive-compulsive disorder (OCD), Tourette's syndrome, Parkinson's disease, and Huntington's disease. Although the actual pathologic mechanisms have not been clarified in each type of disorder, the catecholamine and indoleamine systems of the brain have been implicated in all of them. Anatomic evidence indicates that the corpus striatum, globus pallidus, and their connections with the frontal lobes and thalamus are important to the pathophysiology of movement disorders, mood disorders, subcortical dementia, obsessive-compulsive disorder, psychosis, and sleep disorders. There is also considerable overlap in the pharmacological treatment of these conditions, and this area is a common clinical and theoretical meeting ground for psychiatrists neurologists.
Parkinson's Disease
There are three major symptoms of Parkinson's disease (PD): tremor, bradykinesia, and postural instability. Rigidity, a physical sign, is also characteristic.
P.178
All these are the result of dopamine deficiency. The tremor of parkinsonism occurs mainly when the patient is resting or holding sustained postures. It is dampened during voluntary movements. For this reason, of the three cardinal symptoms, tremor interferes least with normal motor functioning. The tremor of Parkinson's disease is absolutely characteristic, and there only one other condition that can be confused with it, and that is the extrapyramidal side effects of dopamine receptor blocking drugs. Most of these are neuroleptics, but metoclopramide (Reglan) and prochlorperazine (Compazine), common remedies for nausea, also can produce all symptoms of PD, including resting tremor.
Bradykinesia is best defined as slowness in carrying out motor acts, initiating and sometimes in arresting movements. It can seriously impair functioning and makes it difficult for a patient to be dexterous both in fine and gross motor acts, though when it is mild, the disability imposes is often misunderstood, by patients and physicians, to be the result of normal aging or arthritis. Brady-kinesia causes PD patients to delay a few seconds before they can begin walking. This is especially noticeable when they first rise from a seated position or when they change the direction of gait. Sometimes freezing occurs under these circumstances. Some patients experience freezing in doorways. This feature, really a form of gait apraxia, is also seen in patients with frontal lobe dysfunction who do not have dopamine deficiency. Patients with PD may lose associated or spontaneous movements such as swinging arms while walking. The gait of a typical PD patient is small-stepped and narrow-based. Patients with degeneration of nerve cells that are outside the dopamine system tend to have a gait that is small-stepped but broad-based.
Postural instability is the most disabling symptom. An inability to adjust rapidly to postural changes may result in frequent falling and serious injury. Sometimes patients take several short, hesitant, “stuttering” steps (marche a petit pas, festinating) when they start walking or when they turn, and falling that is caused by this can be the cause of serious injuries.
Other clinical features of PD that relate to the three cardinal symptoms are expressionless features, a feeling of weakness and of being slowed, flattening and weakness of the voice, diminished dexterity, micrographia, and cogwheel rigidity. Patients can have tremor without the other symptoms of PD. They may also have bradykinesia and/or postural instability without tremor. Symptoms can be unilateral, confined to the arms or to the legs without involvement of rest of the body or may be generalized. Patients whose symptoms commence with tremor have the best prognosis: 80 percent do not become demented or incapacitated motorically. Dementia and irreversible motor symptoms eventually develop in most of those who never have the typical resting tremor (Rajput et al., 1993).
Mostly sporadic, PD is rarely inherited as an autosomal dominant. When this is the case, onset of the disease can be quite early, in second or third
P.179
decade. Ordinary PD begins at age 59 on average, and it affects approximately 1 percent of the population over the age of 60.
While the term Parkinson's disease should be reserved for conditions that result from deficiency of dopamine in the brain, it is applied practice to both those patients who have pure dopamine deficiency and those motor symptoms (bradykinesia, postural instability) that do not result from dopamine deficiency but from the degeneration of other portions the extrapyramidal system. When most of the motor symptoms, but not all, reverse with dopamine replacement therapy, the syndrome may be called Parkinson's Plus The word “plus” indicates the involvement of cells outside dopaminergic system.
Many degenerative diseases primarily affect regions of the nervous system that lie outside the dopaminergic system. By also affecting dopamine neurons, such diseases can also cause a clinically significant degree of dopamine deficiency. In these cases, we can treat the symptoms that result from dopamine deficiency, but the primary symptoms, the ones that arise outside dopamine system, are usually untreatable. Striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), progressive supranuclear palsy (PSP), multisystem atrophy (MSA), Lewy body dementia (LBD), multi-infarct dementia (MID) are all diseases that result from the loss of neurons outside dopamine system but often produce some degree of dopamine deficiency, and hence can lead to the symptoms of parkinsonism. Only the that derive from dopamine deficiency can be treated with dopamine replacement. When tremor occurs in these conditions, it is usually an intention tremor, not a resting tremor.
Thus, there are four kinds of degenerative conditions that loosely called “Parkinson's.” One is pure dopamine deficiency. This is true PD. It is eminently treatable and has the best prognosis. The second is Parkinson's Plus, i.e., mostly dopamine deficiency mixed with symptoms that arise from disease of the nervous system beyond dopamine deficiency. The third (SND, OPCA, PSP, MSA, LBD, MID, etc.) looks like PD in the sense that there is bradykinesia and postural instability, but these symptoms are only slightly relieved by dopamine replacement therapy as they mostly derive from lesions outside the dopamine system. The same untreatable diseases can also cause Parkinson-like motor disablility and death without ever causing clinically significant dopamine deficiency and dopamine replacement therapy is completely ineffective (Table 5-1).
We do not know if non-Parkinson diseases that can produce dopamine deficiency are separate entities or rather different points in the same spectrum, but lumping all of them under the heading “parkinsonism” has muddied understanding of the course illness and the effect therapy. For example, dementia is feared as the inevitable consequence of PD, though it is unusual in pure dopamine deficiency but common in the others. L-dopa has been mistakenly blamed for the ultimate loss of responsiveness to dopamine replacement therapy and partly for this reason L-dopa is witheld when it would be the most effective
P.180
therapy. The cause of L-dopa unresponsiveness, if it occurs, is likely to be the evolution of dopamine deficiency into one of the other, more malignant forms of parkinsonism. Alternatively, periodic nonresponsiveness could just represent sensitivity to dietary protein in the “on-off” phase of dopamine deficiency. The term end stage Parkinson's has developed two meanings. One use of the term describes a patient with no clinically significant dopamine deficiency but with other brain involvement who is curled into a ball in flexion, helpless, and demented. Dopamine replacement therapy has no beneficial effect but only makes the patient hallucinate more. The other meaning of the term “end stage Parkinson's,” refers to a patient who has essentially no dopaminergic neurons left but
P.181
no other brain involvement. Properly treated for dopamine deficiency, he or she can function normally, motorically, and intellectually, indefinitely.
|
Table 5-1 Parkinsonism |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pathogenesis
Dopaminergic neurons are shaped like a tree. The trunk is the cell body, the root system is comprised of the dendrites which receive impulses from other neurons, and the leaves are the axon terminals through which each cell communicates its messages to other nerve cells. Each cell has thousands of connections with other nerve cells. The dopaminergic axons project from the substantia nigra in the midbrain up to the caudate, putamen, and globus pallidus, to diencephalon, to portions of the frontal lobe, and to the limbic system. Dopamine is synthesized, stored, released, and taken up again (reuptake) by the very dopaminergic axon terminal that released it. Reuptake of dopamine is the main mechanism of dopamine-inactivation. Insufficient dopamine can cause slowness of thinking as well movement (Lees, 1994). In addition to dyskinesia, excessive dopamine can cause racing thoughts, mania, delusions, confusion, and visual hallucinations. Presumably, the cognitive manifestations of dopamine deficiency and overdosage are mediated through dopaminergic projections to the frontal lobe, basal ganglia, diencephalon, and limbic system.
There is some regional variation in the location of lesions that correlates roughly with clinical type. The akinetic-rigid forms of dopamine deficiency correlate with greater dopaminergic cell loss in the ventrolateral part of substantia nigra. The neurons in this area project primarily to the dorsal putamen. The akinetic-rigid forms of PD are more likely to be associated with dementia and to show behavioral-cognitive toxicity with dopamine replacement therapy.
Cell loss in the medial part of substantia nigra seems to have a better prognosis and correlates better with the tremor of PD. The dopaminergic neurons of this area project to the caudate nucleus and anterior putamen. In Parkinson-like syndromes such as MSA there is cell loss in the lateral substantia nigra and transsynaptic degeneration of striatonigral efferents (that remain intact in uncomplicated dopamine deficiency (true PD). There is loss of dopamine receptors as well in the PD-like syndromes that may explain dopamine unresponsiveness (Jellinger, 1999).
L-dopa
The response to dopamine replacement is the most important criterion for differentiating true PD from the more malignant degenerative conditions that can mimic it. Obviously, to treat dopamine deficiency one would hope to use dopamine, but dopamine cannot pass through the blood-brain barrier. Its immediate
P.182
metabolic precursor, dopa, does pass through the blood-brain barrier, and in the brain it is decarboxylated to dopamine. Dopa is administered orally in the levo form as levodopa or L-dopa. We can reduce the amount of L-dopa needed to provide a good therapeutic response by combining L-dopa with another drug called carbidopa. This is a dopa decarboxylase inhibitor that reduces the decarboxylation of L-dopa to dopamine before dopa can reach the brain, thus permitting more of the administered dose L-dopa to reach the brain.
The effect of L-dopa on end-stage PD patients is remarkable. When it was first introduced in the 1960s, totally incapacitated patients, who had been nursing homes for years, could rise again and resume normal motor function. L-dopa is one of the most dramatically effective medications in the history of medicine. It does not lose efficacy with time unless the disease evolves into one of the more malignant, degenerative forms.
It is curious that dopamine can be generated from dopa in severe PD to provide even a short period of normal functioning. After all, if the dopamine neurons have died, where does dopamine synthesis occur? The answer is not known, but presumably dopamine is generated anywhere a molecule encounters a decarboxylating enzyme that can metabolize it. Then the newly generated dopamine diffuses to its postsynaptic receptors (Melamed et al., 1980). The decarboxylating step is nonspecific and not rate-limiting and can be accomplished in the virtual absence of dopaminergic neurons. Thus, administered L-dopa can overcome the inadequacy of dopamine synthesis.
Normally, the inactivation of dopamine after it has interacted with its postsynaptic receptor depends on its reuptake and storage by the dopaminergic neurons. Their loss reduces the brain's capacity to inactivate and store dopamine. The loss of the inactivation mechanism allows higher and more prolonged elevations of dopamine in the immediate vicinity dopaminergic receptors following levodopa administration. This predisposes to toxicity manifested as dyskinesia and hallucinations.
Stages of Parkinson's Disease
Three stages of dopamine deficiency can be differentiated by the patient's response to administered L-dopa: early, moderate, and end-stage (Table 5-1).
Stage I—early dopamine deficiency—mildly symptomatic
There is more than an 80 percent reduction of dopaminergic cells (Hornykiewicz, 1974) but considerable storage capacity remains so that a patient might be given dose of replacement dopa three times a day, once or even every other day with good effect and without causing much variation in the patient's motor function. Once dopamine is released, the remaining dopaminergic neurons can take it up, thereby inactivating it. Extra dopamine can be stored within the dopaminergic
P.183
neurons. At this stage patients cannot tell when a particular dose of L-dopa begins to work or how long the good effect of L-dopa lasts. Their symptoms of parkinsonism may not recur until they have ceased taking L-dopa for 2 to 3 days. Since most doctors prescribe L-dopa on a three doses per day schedule, compliant patients in this stage of illness experience a smooth response to Ldopa that is not linked to the timing of doses. This happy state lasts for 5 to 10 years. Dopamine deficiency advances more quickly when it begins early (fourth or fifth decade) than if it begins in the seventh eighth decade. In general, the older patient at the onset of symptoms dopamine deficiency, the longer first stage of illness lasts.
There is little clinical evidence that treatment with L-dopa hastens the degenerative process in Parkinson's but much has been made of this possibility. The hypothesis that L-dopa is harmful stems in large part from the preclinical observation that the metabolism of L-dopa can generate free radicals. These chemical reactions have been emphasized repeatedly and support the hypothesis that the oxyradicals generated from administered L-dopa attack subcellular organelles and cell membranes and hasten cell death, thereby accelerating the progression of PD. Explanations of how L-dopa-accelerated degeneration could occur have substituted for evidence that this happens (Olanow et al., 1998). Fahn (1996), who reviewed this subject and argued in support of the preclinical studies that indicated L-dopa toxicity, also cited animal studies that had failed to find evidence of such toxicity. Agid (1998) reviewed the literature and found preclinical evidence to be confusing and not compelling with regard the existence of dopaminergic toxicity. Weiner (2000) reviewed all the clinical evidence and concluded that, after all these decades of L-dopa use in PD, there is still no convincing evidence that L-dopa in therapeutic doses is toxic at all or that it accelerates PD progression. Even though L-dopa is tried and true, cheap, effective, and safe, many neurologists prefer not to use L-dopa until it is absolutely necessary, or try to use as little as possible, substituting other less effective, more toxic, more expensive drugs (Frucht et al., 1999; Rascol et al., 2000; Parkinson Study Group, 2000). Yet, there is no evidence that any other compound is superior to L-dopa in slowing the course of PD. has dramatically improved the symptoms of PD and its use early in the course may actually lengthen patients' lives (Diamond et al., 1987).
Stage II—moderate dopamine deficiency—wearing-off—fluctuations of motor activity
This phase of PD is characterized by the wearing-off phenomenon, motor fluctuations that are closely related to the time of L-dopa administration. The wearing-off phenomenon probably reflects disease progression and a decreasing ability of the brain to store dopamine. There is much evidence support the hypothesis that presynaptic failure of dopamine storage explains wearing-off phenomenon and that it is not the result of progressive insensitivity
P.184
or down-regulation of dopamine receptors (Greene, 1988; Sage and Mark, 1994). The evidence that diminished storage capacity of dopaminergic neurons rather than receptor down-regulation is responsible for wearing off includes the following: (1) Patients with wearing-off retain the capacity to respond clinically L-dopa. (2) More frequent dosing of L-dopa is effective in controlling the phenomenon. (3) After an intravenous L-dopa infusion is stopped, fluctuating patients sustain the anti-Parkinson effect of the medication for a shorter period time than do stable patients. (Fabbrini et al., 1988; Mouradian et al., 1988). This is what would be expected if the brain's capacity to retain dopamine were reduced and the capacity to respond dopamine were retained. (4) Positron emission tomography studies with (F)-6-fluorodopa in patients PD have shown less of an accumulation fluorodopa and its metabolites in the basal ganglia of fluctuating patients than in stable patients (Leenders et al., 1986a, b), presumably because there is reduced capacity to store the dopamine that derived from the labelled L-dopa. (5) Deprived of dopaminergic afferents, rat basal ganglia exhibit a diminished capacity to store dopamine (Spencer and Wooten, 1984.) (6) During off periods, patients retain the capacity to respond injections of apomorphine, a dopamine agonist. This indicates that the receptors are functioning normally. (Guttman et al., 1986; Stibe et al., 1988; Wooten, 1988) (7) There are normal to increased levels of dopamine receptor binding sites in the basal ganglia of patients with PD (Leenders et al., 1986a, b).
These observations indicate that postsynaptic receptors are available for dopaminergic stimulation, but the presynaptic storage of dopamine is defective. The hallmark of the wearing-off effect is patient's capacity to tell how long it takes from the time he swallows a dose of L-dopa to the that dose becomes effective in relieving his symptoms (usually about 30 minutes). The patient can also tell how long the therapeutic effect of a particular dose lasts (usually about 3 hours).
Stage III—end stage of dopamine deficiency
This is the final phase of disease when virtually no dopamine storage capacity is left. Rapid shifts occur clinically between on and offperiods. The on state refers to mobility, the off state to immobility. A constant delivery of L-dopa the striatum is essential support continuous dopamine synthesis in the brain that has become totally depleted of its dopaminergic neurons (Sage and Mark, 1994). In the normal brain and even in the moderately affected parkinsonian brain, an excess of dopamine is stored in the presynaptic neurons and is available for release should the delivery of L-dopa to the brain be temporarily interrupted. In Stage I and II patients, the stores of dopamine can support movement for a little while if the next L-dopa dose is delayed in entering the brain. In Stage III patients, periods of bradykinesia or freezing (“off periods”) occur abruptly if L-dopa is delayed in crossing the blood-brain barrier.
P.185
There is strong evidence that peripheral pharmacokinetic factors contribute to the complex fluctuations in Stage III patients. A delay the entry of L-dopa into the brain may result from slow gastric emptying L-dopa is absorbed in the small intestine). This can be ameliorated by placing a tube into the duodenum and delivering L-dopa directly in that manner (Sage et al., 1989).
A more important cause of delay between the time administration of L-dopa and the onset of its beneficial effect is lag in the transit L-dopa from the circulating plasma, across the blood-brain barrier, into brain (Nutt et al., 1984). High concentrations of circulating large neutral amino acids (LNAA) in the plasma is the most common reason for this lag. These amino acids are derived from dietary protein and they compete with L-dopa for the carrier that brings both L-dopa and LNAA into the brain (Juncos et al., 1987).
The deleterious effect of dietary protein on movement is experienced only in Stage III PD. Immobility in response to high levels of plasma LNAA does not occur in normals or in earlier stages of PD's even though elevated plasma levels of LNAA always slow and reduce the entry of L-dopa into brain (Leenders et al., 1986a, b). Because in Stage III PD there is no dopamine stored the brain, the patient experiences apparently unpredictable episodes of L-doparesistant bradykinesia whenever the plasma LNAA concentration rises above level that prevents L-dopa from crossing into the brain. Freezing of motor functions can be sudden. Like cars that have just run out of gas, patients stop moving. It is seldom possible to raise the blood levels of L-dopa high enough overcome the effect of elevated plasma concentrations LNAAs without also causing severe dyskinesia when the LNAA levels diminish. The combination of high plasma concentrations of both L-dopa and LNAA is probably responsible for the phenomenon called peak dose bradykinesia.
There is a simple explanation for the mysterious sensitivity to L-dopa of Stage III Parkinson's disease patients who develop dyskinesia at lower doses than patients at earlier phases of the disease (Trendelenburg, 1966; Mouradian et al., 1989). The complete loss of the presynaptic dopaminergic cells in Stage III patient results in the loss of modulating dopamine inactivation-storage sequence. Without the inactivating reuptake mechanism and storage, dopamine remains too long at the receptor. This unmodulated increase in dopamine concentration at the postsynaptic receptors results in symptoms of overdosage (dyskinesia, hallucinations) because there is no place to store excess dopamine. Therefore, as the disease advances, patients are increasingly subject to developing alternating periods of being off (Parkinsonian) and on (dyskinetic). It is somewhat counter-intuitive but true that patients seem to become more sensitive to L-dopa as their disease progresses, responding to slight overdosage with marked dyskinesia and/or hallucinations. At the same time, patients experience periods of apparent unresponsiveness to administered L-dopa. The therapeutic window between underdosage and overdosage in Stage III is very narrow,
P.186
the threshold dose to produce dyskinesias is much lower in patients with endstage dopamine deficiency than it is in patients with early dopamine deficiency (Mouradian et al., 1989).
Protein Redistribution Diet
Mena and Cotzias (1975) first suggested that plasma LNAAs, derived mainly from dietary protein, antagonize the clinical effectiveness of oral L-dopa. When Stage III PD patients receiving L-dopa were studied on a high-protein diet, they all remained bradykinetic. On the following day, while they consumed a low protein diet, they became mobile, even dyskinetic, while receiving the same doses of L-dopa. The LNAA level bore an inverse relationship to the clinical status of each patient. The level began to rise within 1 hour after the first high protein meal. When the LNAA plasma level increased to 2.5 times fasting levels, all patients became immobile. When the LNAA plasma level dropped, bradykinesia lessened or patients became dyskinetic (Pincus and Barry, 1987a, 1987b, 1987c, 1988).
Since the publication of the first of these reports, basic findings have been confirmed independently by many groups (Eriksson et al., 1988;Riley and Lang, 1988; Tsui et al., 1989; Bracco et al., 1991). The longest follow-up periods are now 14 years. There has been no tendency for the diet to become less effective over time as a means of maximizing the efficacy L-dopa (Karstaedt and Pincus, 1992).
Pharmacological Treatment
There are a number of other antiparkinson agents that commonly prescribed. These fall into different categories depending on their mechanism of action: dopamine uptake inhibitiors, dopamine agonists, monaminoxidase inhibitors, and catechol O-methyltransferanse inhibitors.
Belladonna compounds—Trihexyphenidyl (Artane) and benztropine (Cogentin)—may be mildly effective in Stage I PD. Belladonnas reduce tremor and some of the other Stage I symptoms. They are relatively ineffective in relieving the Parkinson's symptoms of patients with Stage II and Stage III PD. Yet they are much more effective in reversing all the symptoms of neuroleptic druginduced parkinsonism that results from dopamine receptor blockade.
Belladonnas inhibit dopamine reuptake (Coyle and Snyder, 1969). By blocking the inactivation of released dopamine, belladonna compounds can overcome some symptoms of patients with mild, Stage I PD. Dopamine reuptake inhibition is not an effective mechanism for relieving the symptoms of advanced PD because there are few dopaminergic neurons left on which such medications can act (Taylor et al., 1991).
P.187
The balance theory
The belladonna drugs are anticholinergic and many neurologists mistakenly attribute their anti-Parkinson activity to their anticholinergic action, envisioning such compounds as restoring a balance between acetylcholine and dopamine. The concept is that acetylcholine dopamine are normally in balance. In PD, there is thought to be an imbalance between the two transmitters because dopamine is depleted and acetylcholine normal. By reducing acetylcholine levels, according to the balance theory, a new, lower balance can be achieved with dopamine. Consequently, motor activity will return to normal. The balance theory fails to explain the mechanism by which drugs with anticholinergic effects have an impact on PD.
A brief review of the pharmacology three classes anticholinergic drugs indicates that anticholinergic activity is irrelevant to PD. Neuroleptics, such as chlorpromazine, are strongly anticholinergic but cause parkinsonian symptoms. Belladonna compounds, like trihexyphenidyl and benztropine, are powerful anticholinergic agents but relieve parkinsonian symptoms. Tricyclic antidepressants (TCA), like amitriptyline, do not affect PD symptoms at all, even though they are strongly anticholinergic. The interaction of drugs with dopaminergic systems is the only explanation for the differential effects of these classes drugs on PD. Neuroleptics block dopamine receptors and therefore induce parkinsonism or worsen its symptoms. Belladonna compounds block dopamine reuptake and therefore slightly improve some symptoms of PD in the early stage, whereas TCAs have no effect on the dopaminergic systems. Tricyclic antidepressants block serotonin and norepinephrine uptake. They are antidepressants with no effect on the motor symptoms of PD. The balance theory recurs in discussions of chorea, psychosis, and the interaction of drugs. It is woefully inadequate to explain the phenomena to which it has been applied.
Amantadine probably inhibits the dopamine uptake mechanism (Brown and Redfern, 1976; Metman et al., 1998, 1999) and is mildly effective in relieving bradykinesia and tremor in mild Parkinson's disease as it prolongs the duration of action of released dopamine. It is relatively ineffective in relieving the symptoms of severe Parkinson's disease where there are few dopaminergic cells left on which to act. Amantadine also effectively reduces L-dopa-induced dyskinesia and is useful in late stage Parkinson's disease for this purpose. This effect counter-intuitive and was first reported 34 years after the introduction of amantadine for the treatment of Parkinson's disease. This is an example how physicians often do not see what they expect to see. No convincing theory for amantadine's efficacy in treating dyskinesia has yet been offered, though inhibition of NMDA (glutamate) receptors has been proposed as a mechanism (Kornhuber et al., 1995; Verhagen 1998).
Dopamine agonists including the oldest such agent, bromocriptine (Parlodel), and three newer ones, pergolide (Permax), ropinerole (Requipp), and pramipexole (Mirapex) directly activate dopamine receptors. They are not taken up by
P.188
presynaptic cells, need not be released at a particular time, and require no inactivation mechanism. Theoretically, they should be very effective in late PD, but unfortunately, they are poor substitutes for dopamine and are much less effective in relieving PD symptoms. They are used most effectively early PD. Because of their ineffectiveness compared with L-dopa, they also cause less dyskinesia. Bromocriptine is inferior to the others. No study has compared the three newer agonists. All are prone to causing unacceptable cognitive side effects and somnolence, a potentially serious problem for automobile drivers (Lachenmayer, 2000).
The monamine oxidase inhibitor (MAOI), selegiline (Deprenyl, Eldepryl), inhibits beta MAO. This produces a minimal symptomatic benefit by increasing the intracellular dopamine concentration in patients with some dopamine neurons left. The drug is now being used clinically in an attempt to prevent PD from getting worse, but the research on which this is based has been severely criticized (Landau, 1990).
Catechol-O-methyltransferase inhibitors (COMTIs) inhibit the enzyme catechol-O-methyltransferase that is responsible for the degradation of L-dopa. By reducing L-dopa breakdown, COMTIs elevate blood levels of L-dopa and prolong this elevation. The use of tolcopone with L-dopa has allowed patients with fluctuating responses to L-dopa to take L-dopa less frequently (Martinez-Martin and O'Brien, 1998). The deaths from severe liver failure of several patients who were taking tolcopone has dampened enthusiasm for this drug despite the advantages it provides. Encapone (Comtan) has largely replaced tolcapone as a COMTI. Encapone is effective and safe but has a relatively short half-life and must be taken up to eight times a day.
Surgical Treatments
Transplants
Transplantation of fetal cells is based on the concept that the embryonic cells can grow in the striatum and begin to produce dopamine. There have been some reports of clinical benefit and also reports disabling dyskinesias (Olanow, 2001). However, the transplant would only function as a biological dopamine pump. It could be efficacious only in simple dopamine deficiency and could not relieve symptoms that L-dopa failed to reverse. If L-dopa relieved a patient's symptoms, there should be no need for the transplant.
Pallidotomy/thalamotomy
These procedures relieve dopa-induced dyskinesia, permitting the use of more L-dopa for the treatment of PD symptoms, without resort to a protein redistribution diet. Though the positive effects of thalamotomy have not been fully explained, the procedure is based on evidence that the globus pallidus is over active in PD. Ominously, word fluency, only
P.189
function commonly tested that is mediated by the frontal-basal ganglia-dorsal thalamic circuit, has been significantly and permanently affected by pallidotomy (Junque et al., 1999). Major complications have occurred in up to one third of operated patients (Shannon et al., 1998).
Brain stimulation
A permanent in-dwelling electrode placed into the subthalamic nucleus or elsewhere bilaterally and stimulated can reduce tremor some of the more disabling symptoms PD. It is a reversible procedure and therefore safer than pallidotomy in the sense that the stimulator can be turned off and the electrodes removed. Neuropsychological testing of executive functioning preoperatively and then postoperatively has not been performed systematically. Tests of posterior brain function have been carried out with generally good results after surgery. Careful neuropsychological testing during stimulation has not been reported yet.
Psychiatric Symptoms in Parkinson's Disease
Depression
There is great variability in the reported incidence of depression in PD. The mean incidence is often cited as 40 percent, but the reported rates vary from 4 to 70 percent in different studies (Cummings, 1992). In part this variability may reflect the difference between samples of specialized clinical populations and community-based surveys. In a recent community-based survey of patients with PD only 7.7 percent of 245 met the criteria for major depression (Tandberg et al., 1996). This is a figure that reflects incidence. There is a lifetime prevalence of 6 percent major depression in community samples (Blazer et al., 1994), which would make the incidence of depression in PD not necessarily more frequent then one would expect a normal population.
In some measure, the widely varying reports of the incidence and prevalence of depression in PD patients can be explained by the overlapping character of the physical symptoms of PD and depression. For example, slowing psychomotor functions, problems with eating and sleeping, a negative self-image a gloomy outlook about the future may all be taken as signs of depression on some standardized depression interviews and rating scales. When a PD patient complains of such symptoms as feeling weak, lacking energy, and useless, it is likely that the symptoms result from PD rather than depression. Thus, symptom checklists for depression may contain a bias towards in PD patients. Taylor et al. (1988) confirmed that the depressive symptoms of which PD patients complain are not typical of depression. Depressed PD rarely mentioned guilt or self-deprecatory feelings, crying, anger. Yet there is considerable support for the concept that patients with PD are predisposed to milder
P.190
depression. The more severe the motor and cognitive symptoms of PD, the likely the patient is to experience some symptoms of depression (Kuzis et al., 1997; Lauterbach et al., 1997; Tandberg 1997).
Depression, however, is not a simple reaction to having PD. Some PD patients can be very mildly affected motorically but have severe depression, and patients with severe PD may have no depression at all. It is conceivable that depression in PD is a manifestation of Parkinson's Plus; as such, it would be closely related to the underlying neuropathological process rather than to environmental or psychological factors. A Mini-Mental Status Examination score below 24, indicating dementia, increases the probability of major depression in PD patients by a factor of 6.6 (Tandberg et al., 1997).
L-dopa does not relieve depression in PD. It significantly increase brain levels of norepinephrine, its major metabolite (Maricce et al., 1995). However, levels of the norepinephrine metabolite, methoxyhydroxyphenethyleneglcol (MHPG), are elevated diffusely in the central nervous system after treatment with L-dopa. This indicates an increase in norepinephrine turnover. Exogenous L-dopa in cats decreases norepinephrine levels the hypothalamus. This may be the result of a dopamine-induced increase in norepinephrine release. L-dopa has long been known to induce manic episodes in manic-depressive patients (Murphy et al., 1971). Generally, the depression can be relieved by SSRIs, and are preferred, as the anticholinergic side effects of many tricyclic antidepressants may lead to delirium (Lieberman, 1998). The depressive symptoms most likely result from some abnormality of the serotonin or norepinephrine systems, since the original papers describing catecholamine and indolamine abnormalities in PD described 50 percent or so depletions of norepinephrine and serotonin along with even more marked reductions in dopamine
Electroconvulsive therapy (ECT) has been used effectively to treat depression in PD patients and may also reduce some of the PD symptoms for a period days. Improved PD symptoms may reflect increased brain levels of anti-Parkinson medications produced by ECT, for ECT transiently makes the bloodbrain barrier more permeable.
Anxiety versus akathisia
Although it has always been difficult to separate anxiety symptoms from depressive symptoms, a 38 percent incidence of anxiety disorders has been found in a small group of well-studied Parkinson's disease patients (Stein et al., 1990; Menza et al., 1993a, b, 1995). This compares to an 11 percent incidence in patients with chronic medical conditions. In our experience, anxiety attacks in PD almost never respond to antidepressants. Anxiety attacks in PD usually represent episodes of akathisia (restlessness) and reflect inadequate amounts of dopamine in the brain. Patients with akathisia complain of shakiness that is internal and cannot be seen by observers. They wish to move about and sometimes ask family members to move their extremities, lest they
P.191
become frozen. Some complain that they cannot take a deep breath and fear they are going to die. It is easy misunderstand these symptoms, and not a few patients have been mistakenly and ineffectively treated with antianxiety drugs to relieve episodes. If the patient is inadequately treated with L-dopa, he or she may have constant anxiety, that actually represents akathisia. This can be debilitating to the patient and to the care giver. Undiagnosed, the constantly complaining patient with akathisia may seem to the physician represent excessively dependent, neurotic, annoying behavior. Limiting protein intake, taking L-dopa regularly on schedule, and using sedative medications after the single high-protein meal are useful management techniques. Sleep abolishes almost all movement disorders including akathisia.
Painful dystonia
Another motor symptom in PD that may lead to an inappropriate consideration of an anxiety or psychosomatic diagnosis is dystonic cramps. These too reflect deficiency of brain dopamine levels. Approximately 25 percent of PD patients who are in the second or third stages disease develop dystonia. Dystonia refers to an abnormality of posture caused by an abnormal, involuntary contraction of a skeletal muscle. There is often a writhing, athetoid component, and sometimes an action tremor. It is not always painful, but usually the cramp caused by dopamine deficiency is painful. This too reflects deficiency of brain dopamine levels. Though it can affect any skeletal muscle of the body, including eyes (oculogyric crisis), dopamine-responsive dystonia has a predilection for the feet and toes, which twist curl, painfully. The cramp often occurs just after or just before the patient takes his medication. This has been called “beginning-of-dose” and “end-of-dose” dystonia. These are equivalent terms. Many patients feel that L-dopa has caused the cramp. Medical personnel can be fooled by this report. In fact, the previous dose of L-dopa is wearing off and the dose that has just been administered (or that is about to be administered) has not yet taken effect. It is the lack of L-dopa, not its use, that is the problem. Dystonia may occur at night when the patient awakens in a relatively unmedicated state. Sleep prevents dystonic cramping. Patients awaken and then develop cramps. Sedatives can help by reducing mid-night awakenings. Taking L-dopa throughout the night on a regular schedule can also prevent dystonic symptoms. This is not very disruptive for those patients who have two or three nocturias. All odd pains in PD patients who are being treated with L-dopa are possible examples of dystonias. Normal GI tests and other negative investigations into the origin of such pains can lead to a mistaken psychiatric diagnosis.
Psychosis
With so many drugs being used to treat PD, it is often difficult differentiate drug-induced delirium from psychosis caused by structural brain disease. L-dopa can cause delirium, psychosis, and mania (Cummings, 1991; Sanchez-Ramos et al., 1996).
P.192
PD patients seem unusually susceptible to confusion and hallucinations postoperatively. Sixty percent of PD patients, undergoing nonbrain surgery, experienced confusion and hallucinations postoperatively. There was no difference whether the anesthesia general or spinal (Golden et al., 1989). There is also an increased incidence of visual hallucinations in forms of mixed PD-like Lewy body dementia that is unrelated to medication and correlates significantly with the severity of the illness, e.g., presence of dementia, advanced age, and history of depression (Stern et al., 1993; Klatka et al., 1996).
All drugs used to treat PD can produce nightmares, agitation, delirium, loose associations, visual and auditory hallucinations, delusions, inappropriate affect. The atropine-like compounds are probably most likely to produce this kind of mental change, especially in older patients, and must be used very cautiously at low doses in PD patients if they are used at all. For this reason, it is wise to start atropine-like medications or any other anti-Parkinson agents with relatively small doses to be sure that the patient can tolerate drug. Because all these medications potentiate dopamine in some way, they can all cause toxic psychosis that shares certain features with schizophrenia, mania, or other psychiatric disorders (Doraiswamy et al., 1995). Most patients who develop hallucinations and delusions while receiving anti-Parkinson medications have some degree of underlying dementia. The new atypical antipsychotics such as clozapine (Clozaril) and quetiapine (Seroquel) have proven effective, without causing increased motor symptoms, in the treatment of both delirium and psychosis PD (Rabey et al., 1995; Sajatovic and Ramirez, 1995; Lieberman, 1998). Dose reduction of the anti-Parkinson dugs, especially L-dopa, should be tried first.
Usually, PD symptoms in psychotic patients reflect the effects of neuroleptics not idiopathic PD. In those patients unfortunate enough to have PD and mania or schizophrenia, L-dopa and other anti-Parkinson medications must be used with great caution in small, gradually increasing doses. L-dopa can precipitate manic episodes in bipolar patients and can worsen the schizophrenic symptoms of schizophrenics.
Dementia
In the last decade, Lewy body disease has been identified as a new degenerative dementia. It overlaps with Alzheimer's and Parkinson's diseases clinically and pathologically. Lewy body disease shows parkinsonian features, often starting in apparently benign fashion with a typical resting tremor that may respond to medical treatment at first. Within months there is progression of the motor symptoms, and they are dominated by postural instability bradykinesia. Treatment with dopamine replacement fails to reverse these more disabling motor symptoms and induces or worsens hallucinations confusion. Early in the course of illness, there is a relatively rapidly developing cognitive
P.193
impairment with significant fluctuation in alertness and a psychosis with recurrent, complicated visual hallucinations and delusions.
The neuropathological hallmark is the presence of intracytoplasmic inclusions, Lewy bodies. These are identical to the inclusions that typically seen in PD. The distribution of these Lewy bodies, unlike that in typical PD where they are limited to the substantia nigra, is widespread throughout the neocortical and paralimbic regions. They coexist with plaques that are typical of Alzheimer's disease (Klatka et al., 1996).
There are many causes of Parkinson-like symptoms other than dopamine deficiency. Cerebrovascular disease and neural degenerative disorders can produce bradykinesia, postural instability, and rigidity. However, the resting tremor that is improved by voluntary movement is virtually pathognomonic of dopamine deficiency or dopamine receptor blockade and is generally a good prognostic sign.
Marder et al. (1995) found that the risk for the development of dementia in a group of PD patients was twice that a matched group without PD. The degree of dementia correlated with the severity the extrapyramidal symptoms. Aarsland et al. (1996) found that 25 percent of the Parkinson's patients they studied had dementia. The dementia was associated with depressive symptoms, older age of onset, postural instability, and akinesia.
Etiology of Neurodegenerative Disorders
The etiology of PD may be quite similar to that other degenerative disorders that involve cognitive decline. Many of these also cause bradykinesia, rigidity, and postural instability. Many degenerative conditions of the brain, including PD, are sporadic, but when they are genetic, they transmitted as autosomal dominants. These include Alzheimer's, disease frontotemporal atrophy (Pick's disease), Creutzefeld-Jakob disease (CJD), spino-cerebellar atrophies (SCA), and Huntington's disease (HD). In each of these diseases, there seems to be an abnormality of a single protein, not necessarily the same protein in each disease, that is a normal constituent of nerve cells. The abnormal protein contains a subtle defect; sometimes only a single amino acid is out of place.
If a protein looked like string of pearls, perfect except for one marred pearl, the problem would be relatively minor. However, proteins are constructed more like slinky toys. If a middle portion were twisted, the whole toy would become useless. Proteins are usually tightly wound in a three dimensional structure. They are constantly broken down and then resynthesized. Because of their distorted shape, the abnormal proteins in the above-mentioned diseases cannot be hydrolyzed by their usual enzymes and hence accumulate within the cell. The accumulation of the abnormal protein, or parts it, leads to death cell.
P.194
In PD, an abnormal form of the intracellular protein, alpha-synuclein, has been found in dying dopaminergic neurons. The accumulation of this abnormal synuclein appears to cause the intracytoplasmic inclusions (Lewy bodies) that characterize the degenerating nerve cells in PD and LBD. In MSA, synuclein deposition is seen in neurons of the hypothalamus and sympathetic nervous system also (Crowther et al., 2000). It is not clear if LBD, MSA, and PD are the same disease with different patterns of deposition synuclein or etiologically if they distinct disorders (Spillantini and Goedert, 2000). Fragments of synuclein exist in the plaques of patients with Alzheimer's disease (Duda et al., 2000). It is not yet clear whether all these diseases have a similar pathogenesis, but the idea that PD and certain syndromes related to it may have a similar etiology with the accumulation of an abnormal protein might explain large overlap among these conditions. (Goedert, 1999)
An abnormal gene for the manufacture of alpha-synuclein appears to be responsible for the rare cases of PD that are inherited by autosomal dominant transmission. The abnormal gene has been identified and the protein product of that gene has been characterized. The abnormal alpha-synuclein can be identified microscopically in brain tissue and it seems identical to that seen in sporadic PD (Gomez-Tortosa et al., 1998). Yet in PD, patients have a normal gene for the production of alpha-synuclein. How the brain cells of genetically normal patients can make the abnormal form of alpha-synuclein is a puzzling subject of current research, and one hypothesis is that a form prion disorder akin to the one that causes CJD and mad cow disease may be responsible (Johnson, 2000). Another idea is that the abnormality resides in the catabolic enzymes that are supposed to break down the affected proteins but cannot do the job.
There may be a similar pathogenesis in HD and SCAs. The accumulation and deposition of protein filaments in HD and some SCAs are the result of trinucleotide repeats (Price et al., 1998). The genes that are located in the nuclei of nerve cells direct the protein synthesis that occurs in these cells. Each gene uses the nucleic acids of its DNA to direct the manufacture a protein. There is a genetic code for each amino acid that comprises a protein. The trinucleotide sequence, cytosine-arginine-guanidine (CAG) in the DNA codes for the amino acid, glutamine, in the protein. If CAG sequence repeats with too frequently in the DNA, resulting protein will have too many glutamine molecules. If there are too many glutamine repeats, a genetic disease results. The location of the gene that contains these trinucleotide repeats determines the disease. The number of CAG repeats determines the severity the illness.
It has been known for a few years that HD is caused by CAG repeats at a particular locus in chromosome 9. As an animal model of HD, knockout mice were prepared. These were developed with the same genetic defect as humans with HD. The mice became ill with an ultimately fatal, degenerative neurological
P.195
disorder. When they were sacrificed and examined, intracellular inclusions were discovered in the mouse brains that had never been described brains of humans who died with Huntington's disease. Human specimens were then restudied. Neuronal intranuclear inclusions that resembled the inclusions seen in the mice were found in the brains of humans who had died HD and SCAs, which are also caused by expanded glutamine repeats. The inclusions in HD had been overlooked for years because no one expected to see them (Davies et al., 1999).
In other degenerative disorders, including Alzheimer's and Pick's diseases, the accumulation of abnormal proteins in filaments presumably causes the affected nerve cells to degenerate. In Alzheimer's disease the filaments involved have been shown to consist of the microtubule-associated protein, tau. Mutations in the gene for tau have also been identified as the genetic causes of some forms of Alzheimer's disease and also frontotemporal dementia (Pick's disease) (Goedert and Spillantini 2000). Another view, however, is that the accumulation of abnormal protein found in the plaques (amyloid precursor protein) causes Alzheimer's disease (Goedert et al., 1998; Lorenzo et al., 2000).
Acute Drug-Induced Movement Disorders
Parkinsonism and many related movement disorders (dystonias, tics, dyskinesias) can acutely be induced by drugs (Armon et al., 1996;Gorell et al., 1988). The drugs that can induce parkinsonism, chiefly antipsychotics such as chlorpromazine (Thorazine) and haloperidol (Haldol), have their primary pharmacological action at the dopamine receptors, competitively blocking them. Dopamine synthesis is faster after administration of these drugs. This has been interpreted as compensation for the receptor blockade. Though the use of neuroleptics is associated with an increase in the total brain level of dopamine, the crucial action of neuroleptics is to reduce dopamine concentration at the postsynaptic receptor site. Antipsychotics can cause pronounced dystonia. Druginduced, acute PD-like symptoms and dystonia can almost always be overcome by the administration of the dopamine uptake inhibitors diphenhydramine (Benadryl), belladonna compounds, or amantadine. If neuroleptics must be administered on a long-term basis, control of the acute drug-induced movement disorders can usually be maintained by the use of a belladonna compound. Dopamine receptor blockers can also acutely induce tics and dopamine agonists, like L-dopa, can acutely cause dyskinesia.
Tardive Movement Disorders
The term dyskinesia should be restricted to chorea induced by a drug. Acute dyskinesia can be caused by too much L-dopa. After months of treatment with
P.196
dopamine receptor blockers, however, a similar movement disorder known as tardive dyskinesia can develop. The major components of tardive are abnormal movements of the cheek, face, and tongue such as smacking, chewing, tongue thrusting, lateral jaw movements, or sucking. Choreoathetoid movements of the extremities and vocalization have also been observed. Most of these symptoms are worsened under emotional stress or during other body movements (Klawans and Barr, 1982; Koller, 1983). How blockage of dopamine receptors over time can lead to dyskinesia is not clear as presumably arises from too much dopamine or too great a sensitivity to it.
Drug use is not the only factor in the development of tardive dyskinesia. A review by Kane et al. (1986) revealed an average 5 percent prevalence of spontaneous dyskinesias in 19 different samples of untreated psychiatric patients (all diagnoses) as compared with a 20 percent incidence in populations treated with neuroleptics. Fenton et al. (1997) compared a group of neuroleptic-naive schizophrenic patients to a large group of other psychiatric patients and found that spontaneous dyskinesias were more common among the schizophrenics, implying that these dyskinesias may be related specifically to the pathophysiology of schizophrenia. Many of the characteristic facial movements tardive dyskinesia were noted in schizophrenics before the advent of phenothiazines (Stevens, 1974). It is possible that tardive dyskinesia could be related to the soft neurological signs found in untreated schizophrenics. These signs include choreiform movements that reflect neurological dysfunction in schizophrenics. Granacher (1981) cautioned against too hastily attributing abnormal movements in a patient taking an antipsychotic drug to tardive dyskinesia, as one may overlook the onset or existence of other movement disorders. The reported incidence in patients receiving phenothiazine chronically varies from 2.9 to 41 percent, probably because of variation in the criteria for diagnosis. Kane et al. (1986) have estimated the cumulative annual risk of tardive dyskinesia in those taking antipsychotics to be approximately 5 percent per year, and in older patients the risk seems to be greater (Caligiuri et al., 1997). When the neuroleptics are used intermittently, there seems to be a much higher incidence of tardive dyskinesias than when they are used continuously. Bipolar patients seem unusually sensitive to the development of tardive dyskinesia, particularly when they are used intermittently (Post and Weiss, 1996; van Harten et al., 1998). The complexity of the neurotransmitter interaction is also highlighted by the fact that tardive dyskinesia has been seen with the use of tricyclic antidepressants (TCA) and with selective serotonin uptake inhibitors (SSRI) (Durif et al., 1995; Vandel et al., 1997). One encouraging aspect of tardive dyskinesia that has begun to emerge is that the symptoms seem to decrease over time after discontinuing or decreasing the dose of medication (Glazer et al., 1990; Koshino 1991). Currently, discontinuation of the dopamine receptor blocker is main treatment for drug-induced tardive dyskinesia and all other movement disorders related to the use of dopamine
P.197
receptor blockers. Substitution for D-2 blockers of atypical antipsychotics like quetiapine and clozapine is probably the best course of action for controlling the psychosis. It sometimes seems to improve tardive movement disorder as well.
Dystonia
Dystonia, sustained muscle contractions that frequently cause repetitive writhing movements and abnormal postures, often associated with intention tremor, is often confused with dyskinesia (see Painful Dystonia, above) (Fahn, 1984). Both can result from long exposure to antipsychotics. Difficult as it can be to differentiate dystonia from dyskinesia, the distinction is important, especially in PD. Dyskinesia is worsened by L-dopa and is relieved withholding L-dopa. Dystonia results from inadequate dopamine replacement therapy. Dystonia in PD is painful, occurs around the time of dosing, and troubles patient more than the care giver. Related or not to dopamine deficiency, dystonia can be relieved by belladonna drugs but sometimes requires enormous doses. Dystonia can be induced acutely by antipsychotic drugs; it can be tardive or it can arise from a disorder of the nervous system that is unrelated to medication.
The classification of dystonias cannot rest on the basis neuropathologic findings because in most cases of idiopathic dystonia the neuropathologic findings have been negative. Patients with progressive generalized dystonia, curled into pretzel-like distortions, may literally die of inanition caused by their disease. Yet neuropathologists describe the brains of such patients after autopsy either as normal or as nonspecifically abnormal (Zeman, 1970; Gibb et al., 1988).
The physical examination is normal too, except for the dystonia itself. There are no Babinski signs. With laboratory testing there are no abnormal blood results, and the EEG and MRI are normal. The tools of diagnosis are exclusively clinical, i.e., bedside observation. As a consequence the term dystonia has had a checkered history. The subject has been reviewed in an extremely clear fashion by Cunningham-Owens (1990) who pointed out that Wilson defined dystonia as any variability in muscle tone whereas Denny-Brown defined it as fixed abnormalities of posture, and Hammond described gross muscle spasms distortions of normal posture. Marsden called athetosis distal dystonia, but Wilson called dystonia proximal athetosis.
Oppenheim gave the condition a formal name, dystonia musculorum deformans. Most references to dystonia are a shorthand for this longer phrase, which embraces its most common form, a disorder of autosomal dominant transmission with incomplete penetrance that is seen primarily in Ashkenazic Jews. Torsion dystonia or torsion spasm are synonyms for dystonia musculorum deformans
Like all movement disorders, dystonia is worse when the patient anxious
P.198
or upset and better when the patient is relaxed. Dystonic movements disappear when the patient is asleep. These characteristics, shared by virtually all movement disorders, have often misled clinicians to mistakenly diagnose dystonia as a conversion (somatiform) disorder. Purely psychogenic causes of dystonia are extremely rare. In the largest published series of patients with dystonia, only 24 of 932 cases were psychogenic (Fahn, 1988). Despite this, approximately about 40 percent of patients with dystonia are given a diagnosis conversion or somatiform disorder at some point (Fahn et al., 1983) but not always by psychiatrists.
Lacking neuropathologic definition, dystonias have been classified by the age of onset, presumed cause, and by the distribution of symptoms. The age of onset is an important feature because of its prognostic implications. The younger the onset the more likely is dystonia to become generalized, spreading from part of the body in which it commences to the spinal muscles and all extremities Generalization of dystonia is particularly likely when the onset of symptoms occurs before 10 years of age. In contrast, generalization is rare when dystonia begins after the age of 40.
There have been over 40 dystonia-associated disorders. Most of these disorders are within the neurological sphere and most very rare. Dystonia is characteristic only of cerebral palsy and Wilson's disease. In dystonia is associated with scarring in the basal ganglia (etat marbre). In Wilson's disease, it has been correlated with cystic degeneration of the putamen.
Based on the distribution of symptoms, dystonia can be divided into five types: focal, segmental, multifocal, generalized, and hemidystonic. The focal symptoms affect only one body area. Blepharospasm, torticollis, and writer's cramp are examples. Segmental dystonia including Meige's syndrome affects two or more contiguous body areas. Multifocal dystonia affects two or noncontiguous body areas. Generalized dystonia affects disparate body areas, and hemidystonia affects limbs, trunk, and/or face on the same side of body.
In addition to their discussion in neurological texts, dystonic symptoms, like writer's cramp, also figure heavily in the pages of psychiatric textbooks as examples of conversion syndromes, illustrating the parallel but separate paths two specialities have often taken in the twentieth-century. Writer's cramp was also considered a hysterical disorder in many leading text books as late 1980.
Idiopathic dystonia is usually slow to develop and worsens over months or years. It is aggravated by voluntary activity and exercises generally make it worse.
Most patients learn some sensory tricks. These include the patient touching his chin, the vertex of his head, back neck with his hand contralateral to the direction of rotation, placing his hand behind back in a “hammerlock” position, yawning, reclining in a particular posture, listening to music, and looking intently at something. Each of these maneuvers, in an individual case,
P.199
may lessen the severity of dystonia and contribute to the mistaken diagnosis conversion disorder.
Focal dystonias may be quite task specific. A patient with writer's cramp, for instance, can drum his fingers well but cannot write. Another may be able to draw but cannot write. A patient who is unable to walk forward may be able walk backward. One of our patients exercises by walking in a large, empty parking lot. He cannot walk counterclockwise around the lot at all. Yet he can walk around it clockwise, but only while he listens to music and reads distract himself.
The treatment of idiopathic dystonia is generally unsatisfactory. Except in those few cases that are responsive to doparnine replacement therapy, symptoms are only slightly ameliorated by medication. Belladonna medications such as trihexyphenidyl and benztropine offer the best relief, but adults do not generally tolerate the doses that are effective in controlling dystonia. These range up to 100 mg per day of trihexyphenidyl (Artane). Children have a much lower incidence of the intolerable anticholinergic side effects belladonnas (memory problems and hallucinations). Peripheral anticholinergic effects in both children and adults can be reversed with pyridostigmine. Less than half the children and somewhat fewer adults with idiopathic dystonia obtain at least moderate benefit from high-dose belladonnas, when they can tolerate them (Fahn, 1988). Focal and some segmental dystonias are best treated with injections of botulinus toxin (Botox). By injecting this into the muscles in spasm, injected muscles are temporarily paralyzed or weakened. Symptomatic benefit can be achieved for 3 to 6 months at a time.
Any drug with dopaminergic blocking qualities can cause or worsen dystonia acutely. Drug-induced, acute dystonia in children is often severe and generalized, whereas in adults acute drug-induced dystonia is usually craniocervical. This parallels the situation in idiopathic dystonia where illness tends to be generalized in children and focal or segmental adults. Drug-induced dystonia develops suddenly, usually within 24 hours after treatment begins. Dystonia can be intermittent with minutes to hours between episodes. Other clinical features of acute, drug-induced dystonia are varied, bizarre, and often terrifying to the patient. They include all the manifestations of dystonia mentioned so far as well as finger and wrist posturing, hyperpronation, hyperextension of the spine (opisthotonos), jaw dislocation, and respiratory stridor. The treatment of acute, drug-induced dystonia is very simple. Belladonnas provide relief within minutes. Benztropine 0.5 mg intramuscularly is all that usually needed. Barbiturates, benzodiazepines, and diphenhydramine have all been used successfully as well.
One of the most distressing features of dopamine-sensitive (Parkinsonian) dystonia is that it can be painful. It is a mercy that the severely deforming postures caused by idiopathic torsion dystonia are usually not painful, although they can be. When there is pain, muscle spasms are accompanied by cramps. The pain
P.200
of curling toes may not look dramatic to the observer but is very real patient, interfering with gait. The painful postures associated with dopamine deficiency often bother the patient much more than observer. (Dyskinesia, a painless condition, is more alarming to the onlooker than patient.) The treatment of Parkinsonian dystonia is dopamine replacement.
Tardive dystonia, which tends to begin in the muscles of face and neck is usually of gradual onset after months or years treatment with dopamine antagonists (Burke et al., 1982). The younger the patient more likely it is to be generalized. In about half of the cases Kang et al. (1986) dystonia was unassociated with other tardive movement problems like dyskinesia. Treatment consists of discontinuation of the offending drug and substitution quetiapine or clozapine for other antipsychotics.
Dystonia and Mental Illness
Because of the uncertainty diagnosis and pathogenesis dystonia, there have been very few detailed reports of psychiatric symptoms in patients with dystonia. It is our impression that in generalized dystonia there are often none. Comorbid depression has been described in a minority of patients with axial dystonia (Bhatia et al., 1997) but without controls. Depression in such patients may be secondary to the deforming movement disorder (Jahanshahi and Marsden, 1992) but this does not explain why most such patients are not depressed. Depression is common in Meige's syndrome, a segmental dystonia (Tolosa, 1981; Sharma et al., 1996) and in other segmental dystonias (Jahanshahi Marsden, 1988, Wenzel et al., 1998). Subcortical lesions that cause dystonia can give rise to depression (Lauterbach et al., 1997) and dystonia has been associated with OCD (Bihari et al., 1992a, b). Focal dystonia (hand cramps) severe enough to require botulinus toxin injections are not associated with significant psychopathology (Grafman et al., 1991).
Chorea
Chorea consists of involuntary, jerky movements the face, tongue, extremities, the trunk, and respiratory muscles. Choreatic movements are rapid irregular, and become more pronounced during voluntary movement and when patients try to maintain a posture. Patients with chorea may try to cover up their disability by blending the pseudopurposeful choreatic movements with normal voluntary movements. Sometimes a patient may demonstrate slight lilt while walking. The gait may have the quality of a dance. Choreatic movements can sometimes be revealed by having a patient squeeze the examiner's fingers. The choreatic movements of the patient's fingers that this accentuates gives the examiner the
P.201
sensation of being milked, hence the term, milkmaid's sign. Patients with chorea are often unable to maintain protrusion of the tongue, and when they put their hands above their heads, choreatic movements of the upper extremities are maximized and the hands tend to pronate (pronator's sign). Choreatic movements and paratonia superimposed on deep tendon reflexes cause the relaxation phase of the reflex to be discontinuous (hung up reflexes).
Chorea and the slower writhing movements of athetosis (with which it is often associated and from which it cannot always be clearly distinguished) may be manifestations of one of several diseases: perinatal brain injury, encephalitis, vascular disease, hypoparathyroidism, Wilson's disease, mitochondrial disorders, and, rarely, brain tumor. The only abnormalities on examination are likely to consist of chorea itself and behavioral-cognitive symptoms. Chorea imparts the appearance of anxiety, which, added to cognitive abnormalities, can easily be misdiagnosed as purely psychogenic.
Huntington's chorea (now called Huntington's disease [HD] as chorea occasionally may not develop) is a degenerative disease of the brain involving the frontal cortical mantle as well the basal ganglia. Because of prominent involvement of the caudate nucleus and putamen in this disease, it has been suggested that chorea may be related to pathology of striatum. It would, however, be a mistake to identify chorea with the pathology of the striatum solely. There are extensive striatal connections to the cortex, globus pallidus, and thalamus. Chorea may be the result of an interruption or imbalance between other neural systems and the striatum. Unilateral lesions of the ventral-lateral thalamus and subthalamic nuclei in man and in monkeys sometimes produce choreatic movements. Chorea in such cases is believed to be the result of loss of inhibiting influences on the globus pallidus. Lesions in the dorsal caudate and putamen have been described in oral-facial dyskinesia, a localized chorea (Altrocchi and Formo, 1983).
Virtually all the diseases in which chorea occurs may be associated with severe emotional disturbance. Roughly half of the patients with HD present with psychiatric symptoms and half develop psychosis at some point in the illness. The mental symptoms of 25 percent are indistinguishable from the symptoms of schizophrenia (Heathfield, 1967).
A review of the behavioral changes associated with HD (Mendez, 1994) indicated that mood disorders are the most common behavioral (23%, including mania in 4%), followed by personality changes (20%) and schizophrenia (8%). The main personality change is apathy; this often manifested as withdrawal from activities and social relations. Disinhibited behavior has also been described where the patients become impulsive, erratic, and irritable with poor judgement and at times demonstrate explosive behavior. This often leads to antisocial behavior. Compulsive rituals and obsessive thinking are also manifestations of cognitive abnormalities in HD. The most common cognitive
P.202
changes in HD are problems with attention, executive functions, memory, motor learning, and decreased verbal fluency; language is usually spared. Thus, the pattern of abnormality the dementia is more frontal-subcortical than posterior parietal-temporal. In some cases the cognitive and behavioral changes occur long before the motor changes. In many cases, though, degree of dementia correlates with the severity of the chorea (Webb and Trzepacz, 1987).
Emotional disturbances also frequently accompany Sydenham's chorea, a major manifestation of rheumatic fever (Goldenberg et al., 1992). The emotional instability that starts with Sydenham's chorea may persist for many years, long after the chorea has resolved (Freeman et al., 1965). Residual chorea also can persist for years, but in many Sydenham's patients, the use of stimulant drugs, such as amphetamines or, in female patients, pregnancy, can precipitate the recurrence of chorea. These induced recurrences chorea can occur in patients who have enjoyed a total remission of all the motor symptoms Sydenham's chorea for many years. Sydenham's survivors also show significant elevations in the psychotic tetrad on the MMPI, suggesting that they have a persistent dopaminergic sensitivity (Nauseida et al., 1983). Psychosis is a frequent, though not a constant, concomitant of chorea, irrespective the cause chorea.
Treatment
The drugs that help alleviate chorea can induce parkinsonism, that is, reserpine, phenothiazine, and the other D-2 receptor blockers as well alpha-methyl dopa treatment (a-MPT, Aldomet). As noted above, all these drugs reduce dopamine concentrations: reserpine by releasing stored dopamine, phenothiazine and related compounds by competitively blocking dopamine at its receptor sites, and a-MPT by blocking dopamine synthesis. Amantadine is the most effective drug for suppressing chorea but the mechanism for this effect is not known.
Drugs that potentiate catecholamine activity increase choreatic activity. These include the belladonna compounds (Aquilonius and Sjöström, 1971; Klawans and Rubovits, 1972). Of the drugs that make chorea worse, L-dopa is by far the most important. About half of all patients receiving L-dopa in therapeutic doses for PD develop chorea (dyskinesia). L-dopa has been shown to worsen chorea in HD.
Though the effects of amphetamines or cocaine upon chorea have not been systematically studied, patients who have taken overdoses of amphetamines or cocaine, either acutely or chronically, may develop symptoms of restlessness, tremor, motor impersistence, and “jumpiness,” which strongly resemble chorea. Motor signs of amphetamine and/or cocaine overdosage are minor in comparison with the abnormal mental state that they cause, however; paranoia and mania predominate among the symptoms of amphetamine toxicity. Depression (“the crash”) can follow their discontinuation.
P.203
Since chorea is improved by drugs that have an antidopaminergic effect and is made worse or induced by drugs that augment catecholamine activity, chorea could be the result of excessive dopaminergic activity or sensitivity. Seeman and Van Tol (1994), Kanazawa et al. (1993), and Klawans (1970) summarized the pharmacological evidence that this could be true in HD.
When the brains of patients with HD are examined at autopsy, basal ganglia, and especially the caudate putamen, are characteristically depleted of neurons. Despite this serious loss of neurons, the dopamine content the putamen and globus pallidus per gram of remaining tissue has been found to be normal and that of the caudate reduced to approximately 60 percent normal. Since the number of neurons per gram is greatly reduced in HD in these regions, each remaining striatal neuron in this disease may be exposed to a relative excess of dopamine.
Imaging studies have revealed hypometabolism in the caudate early cases of HD and caudate atrophy in moderate to advanced cases (Mendez, 1994). Using recombinant DNA techniques, Gusella and co-workers isolated fragments of chromosome 4 that transmit HD. The defective gene has subsequently been identified. (Huntington's Disease Collaborative Research Group, 1993). The severity of the genetic defect relates to extent repeats sequence: cytosine, arginine, and guanosine (CAG). Precise predictive testing for HD is now available. Some family members at risk for HD want to know whether they have the gene for the disease, which has 100 percent penetrance and expressivity. Others avoid this test, preferring not to know (Wiggins et al., 1992).
Motor Tics, Tourette's Syndrome, and Obsessive-Compulsive Disorder
Recent investigations link obsessive and compulsive symptoms with movement disorders and pathology of the basal ganglia (Berthier et al., 1996). Common features of Tourette's syndrome are multiple motor and vocal tics obsessivecompulsive symptoms (OCD). Tourette's syndrome is a genetic condition in which neuropathologic changes have been described in the basal ganglia (Hyde and Weinberger, 1995a,b). The symptoms of Tourette's syndrome and OCD have been observed to develop following streptococcal infections (Swedo et al., 1997;Kurlan, 1998), which raises the question of whether both conditions are a sequelae of rheumatic fever and in this way similar to Sydenham's chorea. Minor distinctions have been made in the quality of OCD symptoms patients who have both Tourette's syndrome and OCD, as compared with OCD alone (Cath et al., 2000).
Obsessions are recurrent and persistent thoughts (such as fear of contamination, or doubts about locking the house, turning off the stove, etc.), images, or
P.204
impulsive thoughts that are intrusive, unpleasant, often violent. They recognized by the patient as inappropriate. These thoughts cause marked anxiety and distress and can cripple the sufferer by producing an attention disturbance that prevents concentration on any matters besides the obsessive thoughts. Compulsions are repetitive behaviors or mental acts (hand washing, counting, praying, etc.) that are driven by obsessions and lead to rituals. Patients with OCD can be very irritable when their rituals are interrupted or the flow of life impinges on their obsessions. They are under constant stress from own thoughts and engage in compulsive acts to relieve this feeling of stress. The obsessions and compulsions may become increasingly frequent, dominating the patient's life. The symptoms often begin in adolescence, and although there are no gender differences in the prevalence and severity, they occur earlier males (6-15 years) than in females (20-29 years). The lifetime prevalence (approximately 2.3%) is similar in almost all countries (Weissman, 1994).
Functional imaging studies have shown hyperactivity of the orbitofrontal and cingulate cortex in OCD. With successful medical treatment, this hyperactivity diminishes. Structural imaging has shown reduced volume in the caudate nuclei of patients with OCD (Robinson et al., 1995; Rauch, 2000), and, oddly, focal brain lesions involving the frontal, temporal, or cingulate cortex and the basal ganglia can cause (as well as relieve) obsessive-compulsive behavior (Berthier et al., 1996).
Eighty-five percent of patients with OCD experience improvement when treated with SSRIs (Pigott and Seay, 1999). The symptoms of OCD are often quite dose responsive, especially to SSRIs. When the proper is achieved, the symptoms will resolve almost completely, and if the dose is lowered, the OCD symptoms will return. Of those patients who do not respond to medications, 25 percent will respond to surgical lesions placed in the cingulate gyrus or a portion of the orbital medial frontal lobes; sometimes both these areas are lesioned (Jenike et al., 1991; Baer et al., 1995). Other obsessive syndromes also respond to SSRIs. Trichotillomania (compulsive hair pulling) and some body dysmorphia, where the patient is obsessed with idea that his body malformed or ugly, respond to SSRIs (Phillips et al., 1998).
Some dogs will develop obsessive grooming to the point where the licking causes open wounds. Veterinarians call this animal model of compulsive behavior the acral lick syndrome. This condition also responds to SSRIs (Rapoport et al., 1992).
There is as yet little clarity concerning the specific neurotransmitter systems involved in OCD. Although the SSRIs are very effective for obsessive-compulsive behavior and implicate the serotonin system, other classes of antidepressants and even some anticonvulsants have also proved modestly effective for treating OCD. Dopamine antagonists have been useful in the treatment of chorea, psychosis, and manic-like symptoms in HD and for the tics Tourette's
P.205
syndrome, but their effectiveness in the treatment of OCD has been variable. There have been reports that high doses of the atypical neuroleptics improve the symptoms of OCD (Ramasubbu et al., 2000). In general, antipsychotics are more effective for the motor than the cognitive symptoms in HD and Tourette's syndrome. There has been no study of the differential effectiveness atypical and older antipsychotics in Tourette's syndrome, HD, and OCD.
Affective Disorders
The high comorbidity of movement disorders and affective disorders is intriguing. Not only are affective symptoms present in many of the disorders movement but also significant psychomotor symptoms are present in the affective disorders. In affective disorders the motor dysfunctions can range from retardation to agitation. As the same neurotransmitters, particularly the catecholamines and serotonin are important to both motor affective disorders it is fascinating to see how the same biologic systems can cause overlapping but different disorders.
Affective disorder is a ubiquitous condition and a frequent concomitant of many neurological and medical conditions. The major phenomenology of affective illness (depression or mania) is mood disturbance, usually accompanied by a disturbance of sleep, appetite, psychomotor agitation or retardation, and mood consonant thoughts. Depressed thoughts and feelings are usually described as sadness feeling “blue,” “low,” or “gloomy.” Because of the ubiquity these feelings, it is often not clear when they should be considered pathological. Usually, this judgment is made on clinical grounds by weighing such factors as the severity of the symptoms, the amount interference with functioning the individual, the duration of the symptoms, age at which they occur, number of similar previous episodes, and a family history the disorder.
In addition to changes in mood, there are alterations the depressed patient's perception of self and the environment. The significance of a particular life event to which an individual is supposed to be reacting determined only after he becomes depressed. Patients often perceive themselves as being worthless, hopeless, helpless, guilty, and even at times “evil.” Frequently they view their accomplishments as meaningless and neither persuasion nor confrontation with reality can change their attitude. If they are delusional, the delusions usually relate to ideas of bodily illness, decay, or other dismal eventualities. Severe depression can be accompanied by paranoid delusions and even hallucinations. Differentiation from schizophrenia in such cases depends on the presence of depression, a relatively normal premorbid adjustment, and a family history of affective disorder. (In manic conditions, we see the obverse of depressive feelings: euphoria, grandiosity, and a heightened sense of one's abilities.) Sleep,
P.206
appetite, digestion, sexual activity, and psychomotor activity may be disrupted. Sleep disturbances can vary from hyposomnia, difficulty in falling asleep, awakening frequently throughout the night, early morning awakening, or any combination of these, to excessive sleep (hypersomnia). Anorexia and weight loss or hyperphagia and weight gain are common. Decreased sexual interest activity are the rule. Changes in psychomotor function, either agitation or retardation are frequently evident. Agitated patients seem anxious, wring their hands, pace about, and frequently sleep poorly. Psychomotor retardation is characterized by reduced physical and mental activity as well hypersomnia. The slowing of thought processes in retarded depressions may suggest dementia (McAllister, 1983; Emery and Oxman, 1992). Suicidal ideation is common, a very real risk, in severe depression.
If the symptoms of depression are present in mild form and transient (not lasting more than 1 to, at most, 6 months) and closely follow emotionally charged events (usually loss of job, health, or a loved one), the reaction may be considered to be grief or bereavement (Jacobs, 1993). If the symptoms are severe, regardless of the presence precipitating factors, if they persist, and if they interfere with the patient's functioning from day to day, condition should be regarded as depressive illness and should treated. Summing up the symptoms rather than weighing individual symptoms best characterizes the severity of a depressive syndrome. Scales for quantifying the severity and variety of affective symptoms have been devised (Beck et al., 1961; Zung, 1965; Hamilton, 1969). We have found these scales that quantify the extent of depressive symptoms quite useful clinically. They are relatively reliable methods of judging the severity of depression, following the course the disorder, and evaluating therapy.
The duration of an episode and the tendency depression to recur, as well as the severity of symptoms, vary from patient to patient. In some patients, depression occurs as a single episode in an otherwise normal life. Most patients having their first depression have no family history of depression. When the family history is negative, there no way of predicting the course of illness. The chances are that a remission will occur and the symptoms will respond to antidepressant medication. Twenty-five percent of such patients will become depressed again in the future (Blazer, 1994).
Patients who have repeated episodes of affective disorder and their illnesses can be divided into two groups:
P.207
In some bipolar patients, mania is more prevalent, almost to the exclusion of depression, though the opposite may occur.
The improved reliability of the diagnostic process using DSM-III (and it's successors), together with standardized interviewing methods, led to the NIMH-sponsored Epidemiologic Catchment Area Study (ECA) in which 18,000 community members from five different areas in the U.S. were interviewed. One of the more interesting aspects of this study was the finding that in both men and women the prevalence of mood disorder is higher in persons under age of 45 years old than in those over 45 old. Mood disorder has a higher prevalence in women but does not vary by race. Its overall prevalence the ECA study was 6 percent (Blazer et al., 1994).
In a review of follow-up studies unipolar and bipolar affective disorders, Robins and Guze (1972) noted that the median duration of the first attack a depressive illness varied. In unipolar depression, it was 13 months; in bipolar depression, 6 ½ months. The mean duration of manic attacks was 3 ½ months but relapse is less likely. Between episodes of illness, unipolar patients tend to be insecure, sensitive, or obsessional, whereas bipolar patients tend to be more active and sociable.
Affective disorder presents with a consistent and recognizable clinical picture. The symptoms represent disturbances of biologic functions controlled by the brain, e.g., mood, cognition, perception, motor, sexual, sleep, and appetite.
Biologic Changes in Affective Disorders
Perhaps because the psychopharmacological agents that treat affective disorder affect the catechol and indoleamine systems, we tend to think primarily of these neurotransmitters when discussing the biologic changes in depression. However, this ignores a large older and newly emerging literature that demonstrates the wide-ranging biologic changes that are present in affective disorder, e.g., the motor system, cognition, sleep, sexual function, the immune system, and arousal. (Bejjiani et al., 1999).
Structural changes
Minor soft signs of diffuse neurological dysfunction and even electroencephalographic abnormalities, so often present in schizophrenic patients, have also been reported in patients with affective disorder (McAllister, 1983; Emery and Oxman, 1992). Previously, patients with such features were diagnosed as having pseudodementia (see Chapter 4, pp. 160–161, 239–240). However, it is clear that many of these signs central nervous system dysfunctions observed in affective disorders remit as the depressive illness abates.
P.208
Imaging studies of depressed patients have begun to contribute some information on structural and functional changes in depression. In the studies of major depressive episodes (MDE), structural MRI has shown fairly consistently decreased frontal lobe, hippocampal, and basal ganglia volumes. Whereas FMRI and PET have shown decreased activity in the dorsolateral prefrontal cortex and increased activity in the ventrolateral prefrontal cortex and the ventral paralimbic structures. The structural findings have been more equivocal in bipolar patients, whereas the functional changes are similar to MDE (Drevets, 1999; Brody et al., 2001). Interestingly many of the functional changes are reversible with antidepressant treatment and sleep deprivation (Brody et al., 2001). Studies using tryptophan depletion and induced sadness cause the same functional changes as noted in depression (Brody et al., 2001). Magnetic resonance imaging signal hyperintensities in the deep and periventricular white matter, have been noted to occur significantly more frequently in elderly depressives. This finding has been reported less consistently in bipolar patients. These deep white matter hyperintensities have also been described in patients with dementia and cerebrovascular disease so their meaning and specificity is as yet unclear. These findings in the frontal and temporal lobes the basal ganglia provide an anatomical basis for the mood, motor, cognitive, and perceptual symptoms observed in patients with affective disorders (Sobin and Sackheim, 1997). McHugh (1989) described a triad of symptoms in patients with basal ganglia disorders depression, dyskinesias, and dementia. He noted that motor sensory pathways, tracts from the cortical association regions, and the limbic system all funnel through the basal ganglia.
Hypothalamic changes
Many of the long observed sexual, appetite, and sleep disturbances (vegetative changes) in depressed patients can be related to neuroendocrine and hypothalamic changes. Sacher (1967) found that depressed patients have elevated blood and urine levels of corticosteroids. There has been a flood of investigations of neuroendocrine factors in affective illness. After many years of study, Carroll and colleagues (1981) published a paper with definitive title “A Specific Laboratory Test for the Diagnosis of Melancholia.” This paper demonstrated that many patients with affective disorders fail to suppress cortisol excretion, as a normal person would when given dexamethasone. Thus, it not only confirmed Sacher's original findings but also pointed to some defect in the hypothalamic-pituitary axis (HPA). As with many studies of psychopathologic conditions, when the control group was extended to other types of psychiatric patients rather than just to normals, the positive findings became less definitive. Cortisol nonsuppression after dexamethasone has now been noted in a wide range of conditions, including normal health, old age, dementia, OCDs, alcoholism, and weight loss (Amsterdam et al., 1982; Insel et al., 1982; Spar and Grener, 1982; American College of Physicians, 1984). The test may correlate
P.209
with therapeutic outcome in that patients with affective disorder who still fail to suppress after treatment have a poorer prognosis (Nemeroff and Evans, 1984). Although it is clear that the dexamethasone suppression test (DST) is not a specific biologic test of depression, it is also clear that in affective illness there is often a disturbance of cortisol metabolism. This metabolic disturbance returns to normal with remission of the affective symptoms. Corticotropin releasing factor (CRF) levels in depressed patients are consistently elevated (Schatzberg and Nemeroff, 1998). Kurlan et al. (1988) found elevated levels of CRF in the spinal fluid of Huntington's disease patients, correlated with the severity of their depression but there were no significant differences in CSF 5-HIAA levels between the HD patients and controls. There are several studies that now show that elevated cortisol levels are related to childhood abuse and may serve as predisposing factors to depression (Heim et al., 2000; Kaufman et al., 2000).
Hypothalamic dysfunction in depression is further suggested by sleep disturbances, slowed heart rate, lowered body temperature, loss of weight and appetite, disturbances of the menstrual cycle, and impotence frigidity (Hill, 1968). Diminished secretion of gastric juice and saliva, reduced peristalsis, a lower basal metabolic rate have also been noted in affective disorders.
Hypothalamic disturbance is also reflected in the extensive studies of thyroid stimulating hormone (TSH) to a dose of thyrotropin-releasing hormone (TRH), which has consistently shown aberrant responses in 20%–30% of depressed patients. Depressed patients may have normal T3 and T4 blood levels but will have diminished or blunted TSH response to TRH stimulation (Loosen and Prange, 1982). Other studies have shown diminished responses of growth hormone, prolactin, gonadol hormones, CRF, and melatonin in patients with affective disorders (Lewy et al., 1982a, b; Kupfer and Thase, 1983; Gold 1984; Bauer and Whybrow, 1988).
Anxiety and arousal
Affective disorder has always presented with a mixture of depressive and anxiety symptoms (Maras et al., 1996). Consequently, it is not surprising that many depressives manifest a general state of hyperarousal. Both elevated galvanic skin responses and muscle tension have been observed in depressed patients (Whatmore and Ellis, 1962; Whybrow Mendels, 1969). Buchsbaum and colleagues (1971) noted that depressed patients tended to augment the intensity of incoming stimuli.
Sleep
Sleep disturbance is one of the most consistent features of depressive illness. In general, it parallels depression in severity. There is little diagnostic specificity as to the type of sleep disturbance e.g., early morning awakening or difficulty in falling asleep (Hawkins and Mendels, 1966). Hyposomnia is characteristic of most depressive illness. This can be manifested as early morning
P.210
wakefulness, a longer latency of sleep onset, and a decrease in non-rapid-eyemovement sleep, both absolute and relative to total sleep. In contrast other forms of depressive illness, the phase bipolar depressive illness is often characterized by increased total sleep and relative total time spent in the rapid-eye-movement (REM) stage of sleep. There is shortened latency (appearance) of the first REM sleep period in 60 to 90 percent of moderately to severely depressed patients. Conditions such as narcolepsy, drug and alcohol withdrawal, and dementia show a similar pattern (Kupfer, 1983; Nofzinger et al., 1999).
An interesting variant of affective disorder, seasonal reflects a disturbance of circadian rhythms. Longitudinal studies have confirmed that there are a group of patients who are sensitive to the light changes in fall and early winter that lead to depression. Many of these patients can be treated by early morning or evening artificial light that shifts their circadian rhythms (Sakamoto et al., 1995; Schwartz 1996).
Neurotransmitter changes
No single neurotransmitter deficiency has been consistently associated with depression. No single defect, such as the lack of dopamine, as in PD, has as yet been found in any affective disorders. As most of the effective medications affect either norepinephrine or serotonin both, these two neurotransmitters have been studied extensively. To date neither norepinephrine nor serotonin has been found to be exclusively defective in depressed patients. Defects in both preand postsynaptic receptors, reuptake of norepinephrine and serotonin have been found variously in groups of depressed patients. Such findings are often not replicated (Schatzberg and Schildraut, 1995; Maes and Meltzer, 1995). Some of the deficiencies in both neurotransmitters are corrected by antidepressant treatment. Compounds that interfere with the metabolism of norepinephrine and serotonin do not cause depression in normals, but surprisingly will cause relapse in patients treated with antidepressants (Miller et al., 1996; Smith 1997). Dopamine is also reduced in some depressive patients (Wilner, 1995). Decreased serotonergic function has been fairly consistently found in patients at high risk for suicide and those who have actually committed suicide (Mann and Arango, 1999). Although it is clear that these key neurotransmitters are often disturbed in depression, it is not clear if these are causal or epiphenomenona of another process. There is increasing evidence that the antidepressants function at the intracellular level to produce their therapeutic effect. Duman has postulated that chronic antidepressant treatment increases cyclic-adenosine monophosphate (AMP) formation, which in turn regulates monoamine function (Duman et al., 1997). Also neurotrophic factors such as brain-derived neurotrophic factor (BDNF) is up-regulated by either antidepressant or ECT treatment in the hippocampal regions of depressed patients, in a time frame that is also more consistent with the clinical response to antidepressants (Nibuya et al., 1995).
P.211
Immune responses
One of the more exciting areas of research in psychobiology is the increasing amount of data demonstrating that stress and depression diminish the responsivity of the immune system (Ader, 1983; Dubovsky, 1997; McEwen, 1998). Although the results are often conflicting, a significant number of studies show that in depression, natural killer (NK) cells, mitogen-induced T cell activity, and certain lymphocytes are reduced (Herbert Cohen, 1993). The possibility of a relationship between disturbed immune function and affective disorder is also suggested by the increasing number of reports major affective and cognitive symptoms in patients with multiple sclerosis (Klonoff et al., 1990;Nyenhuis et al., 1995; Sadovnick et al., 1996).
The cognitive changes in MS are similar to those found PD and HD patients. However, they represent changes in the efficiency of mental functioning more than an actual loss of function (Caine et al., 1986). Multiple sclerosis patients also have significant elevations in cortisol and CRF, just as has been noted in depressed patients who do not have MS (Fassbender et al., 1998).
Genetics
A recent meta-analysis of the genetic etiology major depressive disorders concludes that major depression results from both genetic and environmental factors, that major depression is heterogeneous, and that there are many pathways leading to depression (Sullivan et al., 2000). These authors also note that few of the many genetic studies met their criteria for inclusion in the meta-analysis (clear diagnostic criteria, actual interviews, distinctions made between bipolar and unipolar depressions, etc.), but of the six twin studies that did so the heritability of major depression in monozygotic twins was 31%–42% and of bipolar disorder approximately 70 percent. There was no evidence for gender differences in heritability even though the incidence of depression is greater in women. Sullivan and his collegues also found that major depression runs in families (15%-21% risk first-degree relatives of patients with major depression); however, they could not distinguish genetic from enviromental influences. There is evidence of specificity in the transmission both bipolar and unipolar depression as the rate of bipolar disorder in offspring unipolar depressives is about half that of bipolar probands. The best estimates risk for offspring of bipolar probands is 12 percent and for major depressive offspring approximately 7 percent (Merikangas and Kupfer, 1995).
Most recent molecular genetic studies have involved bipolar patients, and to date there has been replication of linkage studies for sites on chromosomes 18 (Berrettini et al., 1994; Stine et al., 1995) and 21 (Straub et al., 1995; Gurling et al., 1995; Detera-Wadleigh et al., 1996). Many other sites have been identified but not replicated, and some studies have confirmed the chromosome 18 and 21 findings (Sanders et al., 1999).
Stress and negative life events
In most affective disorders, stress and negative life events are as critical as a hereditary predisposition. The evaluation of negative
P.212
life events in patients with affective disorder is often difficult, as depressed patients tend to recall mood consonant events. Depressed patients frequently distort life events or overemphasize their unfavorable aspects; these allegedly causal events may actually be a product of the depressive feelings themselves. Fogarty and Hensley (1983) demonstrated that mood influences the retrieval of memories that were encoded during similar mood states; thus, the depressed patient is more likely to recall events from periods of depression. However, negative life events are more frequent in patients with affective disorder. Negative life events, particularly in a person with a family history of depression, are critical to the onset of affective disorder (Cui and Vaillant, 1996; Harkness et al., 1999; Kohn et al., 2001). An intriguing question is whether or not the presence of depression also tends to create negative life events. Cui and Vaillant (1997) assessed 113 normal college men for negative life events. These were followed for 35 years and given systematic psychological assessments. The authors divided negative life events into dependent (self-imposed, e.g., marital separation) and independent (not self-imposed, e.g., death of a relative, illness in a child) and found that the depressed group, compared to a control group, had a higher density of dependent negative life events after the first episode depression. They concluded that affectively disordered patients apparently do generate negative life events.
Whether self-imposed or imposed on them from the outside, it is clear that the person with depression often experiences considerable stress. Possibly as a reflection of this stress, there is an increased mortality in depressed populations (Harris and Barraclough, 1998). This increased mortality is not just as a result of suicide. The suicide rate accounted for less than 20 percent of the depressed patients' deaths (still very high when compared to a 1 percent suicide rate in control samples). The increased mortality rate was caused by cardiovascular disease (but not cancer) (Wulsin et al., 1999).
Is it possible that depression in many instances is a failed generalized response to stress, that after a prolonged period of stress (either psychological or physical) the clinical picture we call depression is really the end result of a failure adaptive mechanisms to stress. In 1973, Akiskal and McKinney (further elaborated in 1984 with Whybrow and recently by McKinney, 2001) postulated that depressive disorders were a general failure of adaptation to chronic stress. They proposed that depression was the result of environmentally induced endogenous factors that caused reversible deficits in the diencephalic structures related to pleasure and reward. Interestingly, most animal models of depression rely on creating continual stress in the animal (Holsboer, 1999). There is considerable biologic evidence the depressed patient's body is responding to great stress. As we have noted, the HPA is altered in depression; both cortisol and CRF are consistently elevated in the CSF of depressed patients. New research has shown that chronic hypercortisolemia alters brain structure, particularly in the hippocampal
P.213
regions (Newport and Nemeroff, 2002). Lesions in the hippocampus could explain the chronicity of depressive reactions, some the imaging findings, and perhaps even the memory cognitive changes observed in depressed patients (Lupien et al., 1998). There is increasing evidence that our treatments for depression decrease the activity of the hypothalamic-pituitary axis and thus decrease the amount of circulating steroids (Romeo et al., 1998). The treatments increase BDNF in the hippocampus and this might repair the steroid-induced damage (Nibuya et al., 1996; Duman 1997). The time frame of these reactions coincides with the 10-day to 2-week time frame for the therapeutic response to antidepressants better then their biochemical effect on neurotransmitter systems, which are complete usually in minutes to hours.
The depression of immune functions in affective disorder could also be related to stress. We now know that stress depresses immune functions significantly (McEwen, 1998). Perhaps the depressed immune function and the added stress of a medical illness in depression increase the morbidity, mortality, and cost of the care of patients with medical and surgical disorders (Kayton, 1998). The incidence of depression in most hospitalized medical and surgical patients is fourto fivefold greater (20%-30%) then the general population (6%).
In summary, then, depressed patients commonly undergo changes in many physiological systems. No single etiological mechanism causing these changes has yet been defined. However, it is clear that depression relates to a genetic predisposition, environmental stressful events, and a cascade of biologic changes. Although DSM-IV has made the diagnosis of affective disorders more reliable, the categorization of affective disorders is still descriptive. Affective illnesses are probably very heterogeneous with regard to etiology. For example, a unipolar depression and the depressive phase of bipolar illness are phenomenologically indistinguishable, but their chains of causation are probably quite different, the similarity may represent limited number of responses the central nervous system to different etiologies.
Treatment
Depression is a common concomittant of neurologial disease. As we note in Chapter 7, depression can be an emotional reaction to the disease; it can be caused by the neurologic disorder; or it can be a recurrent primary psychiatric disorder. The clinical history is one of the key methods of categorizing these. It is also important to examine the medications person is taking before attempting to treat the depression; many of the medications used neurologic conditions can cause depression, particularly anticonvulsants, antiparkinsonian agents, anticholinergics, and muscle relaxants. Medications used for general medical disorders can also cause depression, e.g., antihypertensives, antiarrhythmics, steroids, oral contraceptives, antiemetics and antihistamines (Tucker et al., 1997). There is little difference in efficacy among the older tricyclic antidepressants (TCAs), the selective serotonin reuptake inhibitors
P.214
(SSRIs), and the newer mixed-effect antidepressants (Table 5-2); 60%-70% of depressed patients will respond to any of these drugs. One of the best indicators of which drug to select is whether the patient has responded well a particular drug in the past. With so many antidepressants now available however the choice is often related to potential side effects that one wishes avoid. Although similar in efficacy, the new antidepressants have supplanted TCAs for several reasons: (1) they have fewer anticholinergic and cardiac side effects (2)overdoses of the new drugs are less dangerous (Hirschfeld, 1999). Many pain syndromes and peripheral neuropathies still seem to respond better the TCAs (Stahl, 1998). Each of the new drugs has a very different chemical structure, so there is a real advantage in changing medications if one does not work (this was not the case with many of the TCAs). For instance, going from fluoxetine to venlafaxine, mirtazapine, or sertraline, etc. can often improve the clinical effect (Thase, 1995). Perhaps the two most common reasons for the antidepressant failure are using too low a dose and not treating the patient for a long enough period. Whichever antidepressant is chosen, the dose should be gradually built up to maximum (if there is no clinical response) and the patient kept at a maximum dose for 4-8 weeks A major problem with the SSRIs and the other new drugs is that they inhibit the cytochrome P450 system and thus can seriously affect the metabolism and subsequent blood levels of medications used for neurologic disorders such as anticonvulsants, benzodiaepines, tacrine, coumadin, beta blockers, etc. Consequently, any time one of these new antidpressants is used, a check should be made for potential drug interactions with other drugs the patient is currently taking (Nemeroff et al., 1996). The primary side effects of the SSRIs and the newer antidepressants are gastrointestinal (nausea vomiting, flatulence), CNS (headache, nervousness, tremor, sleep disurbance), and sexual dysfunction (decreased libido, arousal and delayed ejaculation or orgasm). Bupropion, nefazodone, and mirtazapine have the least effects on sexual function (Dewan and Annand, 1999). Cognitive psychotherapy has proven to be quite effective as both an adjunct and a primary treatment for depression, and has replaced many of the more insight-oriented therapies (Horton et al., 1992).
Conclusion
Parkinson's disease is the model for disorders of catecholamine systems because its pathogenesis is best understood. The primary symptoms of dopamine deficiency (resting tremor, bradykinesia, and postural instability) can be reversed with dopamine replacement; hence the primary treatment is with L-dopa. Some patients with dopamine deficiency also have symptoms that derive from dysfunction of other portions the nervous system outside the dopamine system.
P.215
P.216
These symptoms do not resolve with dopamine replacement. As the degeneration of the dopaminergic cells advances, changes must be made in the schedule of L-dopa administration and the diet to maintain a smooth response. All the drugs that relieve the symptoms of PD are believed to potentiate concentration of dopamine at its receptors.
|
Table 5-2 Antidepressant Drugs |
||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
Clinicians frequently misattribute certain symptoms of dopamine deficiency to psychological reactions, chiefly depression. There is probably some increase in the prevalence of depression in PD but a kind pseudodepression is very common as well. The overlapping characteristics of depression and PD may explain the confusion. If such symptoms as decreased energy, motivation, and initiative, increased sleeping and contentment at doing nothing do not respond to dopamine replacement or antidepressants, they probably derive from degenaration of the frontal-thalamic projections that pass through the corpus striatum. As such, these symptoms constitute not the well-known pseudodementia of depression but the pseudodepression of frontal dementia.
Another easily misdiagnosed symptom of dopamine deficiency is akasthisia. This presents as panic attacks that are associated with “restless legs.” Along with painful, dystonic cramps, akasthisia tends to occur as the preceeding dose of L-dopa has worn off. For this reason, both akasthisia and dystonic cramps are more common in the evening and at night. Neither responds to antidepressants; both respond to dopamine replacement therapy, to benzodiazepines, and to sleep.
Psychosis, confusion, and visual hallucinations can be the result of neuronal degeneration outside the dopamine system and are encountered in patients who also have dopamine deficiency. Psychosis with visual hallucinations, for example, characteristically occurs early in the course of Lewy body dementia. Usually, however, psychosis in PD patients reflects the toxicity of anti-Parkinson medications, all of which can cause psychosis and all of probably potentiate the concentration of dopamine at receptor sites. Only two atypical antipsychotic drugs (clozapine and quetiapine) can control the toxic psychosis of anti-Parkinson drugs without exacerbating the symptoms of dopamine deficiency. Presumably these two drugs control psychosis in some other way than by blocking D-2 receptors. D-2 recptor bockade is the leading mechanism of antipsychotic action of most neuroleptic drugs most which can induce parkinsonism and acute dystonic reactions. Because they block dopamine uptake (inactivation), belladonna compounds and diphenhydramine can reverse such acute reactions.
Almost all the anti-Parkinson medications can cause or exacerbate chorea. This form of acute dyskinesia is usually of more concern to the care giver than to the patient. It is not painful and is the worst when the previous dose of L-dopa is at peak levels. The one exception to the rule amantadine, a weak anti-Parkinson drug, which currently has as its main clinical role the control of chorea. It effectively ameliorates the acute dyskinesia caused by L-dopa, the
P.217
tardive dyskinesias caused by prolonged treatment with antipsychotic drugs, and the chorea of Huntington's disease. Its mechanism action is not known. Chorea, whether drug induced or the result of intrinsic brain disease, is often associated with psychic symptoms: loose associations, difficulty concentrating, inability to stay on target mentally, impulsivity, hypomania, paranoia, and sometimes frank psychosis. In some sense, chorea and psychosis are the opposites of PD as both chorea and psychosis can be the result too much dopamine or too great a sensitivity to dopamine. This is an oversimplification but it explains much phenomenology. It is a form of the catecholeamine hypothesis.
Like Parkinson's disease, many dementing disorders can be inherited as autosomal dominants. This list includes Alzheimer's, Pick's, Creutzfeldt-Jakob, Huntington's, and some nondementing genetic diseases (spinocerebellar degenerations). Some nongenetic degenerative diseases (Lewy body dementia, multisystem atrophy) share with the aforementioned conditions intraneuronal accumulation of a protein, different in composition and/or distribution each disease. The protein is usually a portion of, or closely related to, a normal cellular constituent. Evidence has been gathering that indicates these conditions may be caused by improper genetic instructions for synthesizing the protein or disordered enzymes that normally catabolize it.
Idiopathic dystonia, often inherited as an autosomal dominant, is a disabling, chronic movement disorder of unknown etiology. It has no known neuropathology; no abnormal protein has yet been found within the brain associated with it, and no test other than history and physical examination can confirm the diagnosis. Unlike the dystonia of dopamine deficiency, it is usually painless. Symptoms are often bizarre and psychiatric diagnoses almost always considered early in its course. It can involve the entire body or it can be restricted to one side, one body segment, or can even be focal. It is typically unassociated with psychic symptoms, except in one focal form, Meig's syndrome, that has been said to be associated with depression. The medications that relieve it are the belladonna compounds in very high doses and benzodiazepines. The mechanism through which they provide a measure of symptomatic relief is unknown.
Another autosomal dominant condition of unknown pathophysiology is Tourette's syndrome's motor tics and vocalizations. This is often associated with OCD, another genetic disorder of unknown cause. Within living memory both were regarded as unrelated purely psychological disorders. Their association, genetic determination, and response to medication has changed this perception. Tourette's syndrome can be ameliorated by dopamine receptor blockers and OCD can be ameliorated by SSRIs in high doses. Some basal ganglia abnormalities have been described in Tourette's syndrome but these are not sufficiently characteristic that a neuropathologist could make the diagnosis without clinical data. Functional imaging in OCD has revealed hyperactivity the orbitofrontal and cingulate cortex that diminishes with successful treatment. The response of
P.218
OCD to SSRIs, a new class of drugs that was introduced to treat depression, has raised the possibility that pathogenesis of OCD and depression is similar. There is considerable comorbidity, though these disorders are clinically distinct.
According to the catecholamine hypothesis, depression is result of insufficient serotonin and/or norepinephrine and mania is the result of too much one or both of them. This theory explains many facts. In general, drugs that potentiate the concentration of norepinephrine and serotonin at their receptors relieve depression and precipitate mania, but the theory must be incorrect or at least a gross oversimplification as it does not explain all the facts, e.g., the effect of antidepressant medications on catecholamines is established within minutes but their clinical effect does not begin for weeks. No theory has fully replaced the catecholamine hyothesis. Bipolar affective disorder is probably transmitted as an autosomal dominant and other forms of depression may have genetic determinants. Though mood disorders affect the hyothalamic-pituitary axis and the immune system and can be triggered by physical illnesses emotional stress, no confirmatory test has provided a reliable diagnosis.
References
Aarsland, D. E. Tandberg, J. P. Larsen, L. Cummings. Frequency of dementia in Parkinson disease. Arch Neurol 53:538, 1996.
Ader, R. Developmental psychoneuroimmunology. Dev Psychobiol 16:251, 1983.
Agid, Y. Levodopa: is toxicity a myth. Neurology 50:858, 1998.
Akiskal, H., W. T. McKinney. Depressive disorders: toward a unified hypothesis. Science 182:20, 1973.
Altrocchi, P. U., L. S. Fomo. Spontaneous oral-facial dyskinesia: neuropathology of a case. Neurology 33:802, 1983.
American College of Physicians. The dexamethasone suppression test for the detection, diagnosis, and management of depression. Ann Intern Med 100:307, 1984.
Amsterdam, J., A. Winokur, S. Coroff, J. Conn. The dexamethasone suppression test in outpatients with primary affective disorder and healthy control subjects. Am J Psychiatry. 139:287, 1982.
Aquilonius, S. M., R. Sjorstrom. Cholinergic and dopaminergic mechanisms in Huntington's chorea. Life Sci 10:405, 1971.
Armon, C., C. Shin, P. Miller, et al. Reversible parkinsonism and cognitive impairment with chronic valproate use. Neurology 47:626, 1996.
Baer L., S. L. Rauch, H. T. Ballantine Jr., et al. Cingulotomy for intractable obsessivecompulsive disorder. Arch Gen Psychiatry 52:384, 1995.
Bauer, M., P. Whybrow. Thyroid hormone and the CNS in affective illness. Integr Psychiatry 6:75, 1988.
Beck, A. T, C. H. Ward, M. Mandelson, J. Mock, K. Erbaugh. An inventory for measuring depression. Arch Gen Psychiatry. 4:561, 1961.
Bejjani, B. P., P. Damier, I. Arnulf, et al. Transient acute depression induced by highfrequency deep-brain stimulation. N Engl J Med340:1476, 1999.
P.219
Berrettini, W., T. Ferraro, L. Goldin, et al. Chromsome 18 DNA markers and manic depressive illness. Proc Natl Acad Sci USA 91:5918, 1994.
Berthier M. L., J. Kulisevsky, A. Gironell, et al. Obsessive-compulsive disorder associated with brain lesions: clinical phenomenology, cognitive function, and anatomic correlates. Neurology 47:353, 1996.
Bhatia, K. P., N. P. Quinn, C. D. Marsden. Clinical features and natural history of axial predominant, adult onset, primary dystonia. J Neurol Neursurg Psychiatry 63:788, 1997.
Bihari, K., J. L. Hill, D. L. Murphy Obsessive-compulsive characteristics in patients with idiopathic spasmodic torticollis. Psychiatry Res42:267, 1992.
Bihari, K., T. A. Pigott, J. L. Hill, D. L. Murphy. Blepharospasm and obsessivecompulsive disorder. J Nerv Ment Dis 180:130, 1992.
Blazer, D. G., R. C. Kessler, K. A. McGonagle, et al. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry 151:979, 1994.
Bracco, F., R. Malesani, M. Saladini, et al. Protein redistribution diet and antiparkinsonian response to levodopa. Eur Neurol 31:68, 1991.
Brody, A., M. Barsom, R. Bota, et al. Prefrontal-subcortical and limbic circuit mediation of major depressive disorder. Semi Clin Neuropsychiatry 6:102, 2001.
Brown, F., P. H. Redfern. Studies on the mechanism of action amantadine. Br J Pharmacol 58:561, 1976.
Buchsbaum, M., F. Goodwin, D. Murphy, G. Borge. AET in affective disorders. Am J Psychiatry 128:19, 1971.
Burke, R. E., S. Fahn, J. Jankovic, et al. Tardive dystonia: late onset and persistent dystonia caused by antipsychotic drugs. Neurology32:1335, 1982.
Caine, E. D., K. A. Bamfor, R. B. Schiffer, et al. A controlled neuropsychological comparison of Hungtington's disease and multiple sclerosis. Arch Neurol 43:249, 1986.
Caligiuri, M. P., J. P. Lacro, E. Rockwell, et al. Incidence and risk factors for severe tardive dyskinesia in older patients. Br J Psychiatry171:148, 1997.
Carroll, B., M. Feinberg, J. Greden, et al. A specific test for the diagnosis of melancholia: standardization, validation, and clinical utility.Arch Gen Psychiatry 3 8: 15, 1981.
Cath, D. C., P. Spinhoven, B. J. van de Wetering, et al. The relationship between types and severity of repetitive behaviors in Gilles de la Tourette's disorder and obsessivecompulsive disorder. J Clin Psychiatry 61:505, 2000.
Coyle, J. T, S. H. Synder. Antiparkinsonian drugs: inhibition of dopamine uptake in the corpus striatum as a possible mechanism of action. Science 166:899, 1969.
Crowther, R. A., S. E. Daniel, M. Goedert. Characterisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson's disease brain. Neurosci Lett 292:128, 2000.
Cui, X., G. Vaillant. Antecedents and consequences of negative life events in adulthood. Am J Psychiatry 153:21, 1996.
Cui, X., G. Vaillant. Does depression generate negative life events? J Nerv Ment Dis 185:145, 1997.
Cummings, J. L. Behavioral complications of drug treatment of Parkinson's disease. Am J Geriatr Soc 39(7):708, 1991.
Cummings, J. L. Depression and Parkinson's disease: a review. Am J Psychiatry 149(4):443, 1992.
Cunningham-Owens, D. G. Dystonia-A potential psychiatric pitfall. Br J Psychiatry 156:620, 1990.
P.220
Davies, S. W., M. Turmaine, B. A. Cozens, et al. From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model Huntington's disease. Philos Trans R Soc Lond Biol Sci 354(1386):981, 1999.
Detera-Wadleigh, S., J. Badner, J. Goldin, et al. Affected-sib-pair analyses revel support of prior evidence for a susceptibility locus for bipolar disorder, on 21Q. Am J Hum Genet 58:1279, 1996.
Dewan, M., V. Anand. Evaluating the tolerability of the newer antidepressants. J Nerv Ment Dis 187:96, 1999.
Dewan, M. J., V. S. Anand. Evaluating the tolerability of the newer antidepressants. J Nerv Ment Dis 187:96, 1999.
Diamond, S. G., C. H. Markham, M. M. Hoehn, F. H. McDowell, M. D. Muenter Multicenter study of Parkinson mortality with early versus later dopa treatment. Ann Neurol 22:8, 1987.
Doraiswamy, M. W. Martin, A. Metz, et al. Psychosis in Parkinson's disease: diagnosis and treatment. Biol Psychiatry 19:835, 1995.
Drevets, W., K. Gadde, K. Ranga, et al. Neuroimaging studies of mood disorders. In:Neurobiology of Mental Illness, D. Charney, E. Nestler, B. Bunney, eds. Oxford University Press, New York, 1999, pp. 394–418.
Drevets, W. C. Prefrontal cortical-amygdalar metabolism in major depression. Ann NY Acad Sci 877:614, 1999.
Dubovsky, S. Mind Body Deceptions, Norton, New York, 1997 pp. 309–339.
Duda, J. E., V. M. Lee, Q. Trojanowski Neuropathology of synuclein aggregates. J Neurosci Res 61:121, 2000.
Duman, R. S., G. R. Heninger, E. J. Nestler. A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597, 1997.
Durif, F., M. Vidailhet, A. M. Bonnet. Levodopa-induced dyskinesias are improved by fluoxetine. Neurology 45:1855, 1995.
Emery, O., T. Oxman. Update on the dementia spectrum of depression. Am J Psychiatry 149:305, 1992.
Eriksson, T. A. K. Granerus, A. Linde, Carlsson. “On-off” phenomenon in Parkinson's disease: relationship between dopa and other large neutral amino acids in plasma. Neurology 38:1245, 1988.
Fabbrini, G., M. M. Mouradian, J. L. Juncos, et al. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part I. Ann Neurol 24:366,1988.
Fahn, S. The varied clinical expressions of dystonia. Neurol Clin 2:554, 1984.
Fahn, S., Is levodopa toxic? Neurology 47 (Suppl 3):S184, 1996.
Fahn, S. Concept and classification of dystonias. In: Advances in Neurology, S. Fahn, D. Marsden, D., eds. Calnevol. Dystonia, Raven Press, New York 1988 pp. 1–9.
Fahn, S., Generalized dystonia: concepts and treatment. Clin Neuropharmacol 9: (Suppl 2) S37, 1986.
Fahn, S., D. Williams, A. Reches, et al. Hysterical dystonia, a rare disorder: report of five documented cases. Neurology 33 (Suppl 2)161, 1983.
Fassbender, K., R. Schmidt, R. Mossner, et al. Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis. Arch Neurol 55:66, 1998.
Fenton, W. S., C. R. Blyler, R. J. Wyatt, T. H. McGlashan. Prevalence of spontaneous dyskinesia in schizophrenic and non-schizophrenic psychiatric patients. Br J Psychiatry 171:265, 1997.
Fogarty, S. J., D. R. Hemsley. Depression and the accessibility of memories. Br J Psychiatry. 142:232, 1983.
P.221
Freeman, J. M., A. M. Aron, E. Collard, et al. The emotional correlates of Syderham's chorea. Pediatrics 35:42, 1965.
Frucht, S., J. D. Rogers, P. E. Greene, et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 52:1908, 1999.
Gibb, W. R., A. J. Lees, C. D. Marsden, Pathological report of four patients presenting with cranial dystonias. Mov Disord 3:211, 1988.
Glazer, W. M., H. Morgenstern, N. Schooler, et al. Predictors of improvement in tardive dyskinesia following discontinuation of neuroleptic medication. Br J Psych 157:585, 1990.
Goedert, M. Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. Philos Trans R Soc Lond B Biol Sci 354(1386): 1101, 1999.
Goedert, M., M. G. Spillantini. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. Biochim Biophys Acta 502:110, 2000.
Goedert, M., M. G. Spillantini, S. W. Davies, Filamentous nerve cell inclusions in neurodegenerative diseases, Curr Opin Neurobiol 8:619, 1998.
Gold, P., O. Chrousos, C. Kellner, et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Amer J Psychiatry 141:619, 1984.
Golden, W. E., R. C. Lavender, S. Metzer. Acute postoperative confusion and hallucinations in Parkinson disease. Ann Intern Med111:218, 1989.
Goldenberg, J., M. B. Ferraz, A. S. Fonseca, et al. Sydenham chorea: clinical and laboratory findings. Analysis of 187 cases. Rev Paul Med110:152, 1992.
Gomez-Tortosa, E., A. O. Ingraham, M. C. Irizarry, et al. Dementia with Lewy bodies. J Am Geriatr Soc 46:1449, 1998.
Gorell, J. M., C. C. Johnson, B. A. Rybicki, et al. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346, 1998.
Grafman, J., L. G. Cohen, M. Hallett. Is focal hand dystonia associated with psychopathology? Mov Disord 6:29, 1991.
Granacher, R. P. Differential diagnosis of tardive dyskinesia: an overview. Am J Psychiatry 138:1288, 1981.
Greene, P., H., Shale, S. Fahn. Experience with high dosages of anticholinergic and other drugs in the treatment of torsion dystonias. In:Advances in Neurology, S. Fahn, D. Marsden, D., eds. Calnevol. Dystonia, Raven Press, New York, 1988, pp. 547–556.
Gurling, H., C. Smyth, G. Kalsi, et al. Linkage findings in bipolar disorder. Nat Gen 10: 8, 1995.
Guttman, M., P. Seeman, G. P. Reynolds, et al. Dopamine D2 receptor density remains constant in treated Parkinson's disease. Ann Neurol 19:487, 1986.
Hamilton, M. Standardized assessment and recording of depressive symptoms. Psychiatr Neurol Neuroclin 72:201, 1969.
Harkness, K., S. Monroe, A. Simons, et al. The generation of life events in recurrent and non-recurrent depression. Psychol Med 1:135, 1999.
Harris, E. C., B. Barraclough. Excess mortality of mental disorder. Br J Psychiatry 173:11, 1998.
Hawkins, D. R., J. Mendels. Sleep disturbance in depressive syndromes. Am J Psychiatry 123:682, 1966.
Heathfield, KWC. Huntington's chorea: investigation into the prevalence of this disease in the area covered by the North East Metropolitan Regional Hospital Board. Brain 90:203, 1967.
P.222
Heim, C., D. Neuport, S. Heit, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284:592, 2000.
Herbert, T, S. Cohen. Depression and immunity. Psychol Bull 1133:472, 1993.
Hill, D. Depression: disease, reaction or posture. Am J Psychiatry 125:445, 1968.
Hirschfeld, R. Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. J Clin Psychiatry 60:326, 1999.
Horton, S., R. DeRubeis, M. Evans, et al. Cognitive therapy and pharmacotherapy for depression. Arch Gen Psychiatry 49:774, 1992.
Holsboer, E. The rationale for cortiotropin releasing hormone receptor antagonists to treat depression and anxiety. J Psychiatr Res33:181, 1999.
Hornykiewicz, O. The mechanisms of action L-dopa in Parkinson's disease. Life Sci 15:1249, 1974.
Huntington's Disease Collaborative Research Group. A novel gene containing a trinu-cleotide repeat that is expanded and unstable on Huntington's disease chromosomes Cell 72:971, 1993.
Hyde, T. M., D. R. Weinberger. Tourette's syndrome. JAMA 273(6):496, 1995a.
Hyde, T. M., D. R. Weinberger. Tourette's syndrome: a model neuropsychiatric disorder. JAMA 273(6): 498, 1995b.
Insel, T. R., N. H. Kalin, L. B. Guttmacher, et al. The dexamethasone suppression test in patients with obsessive compulsive disorder.Psychiatry Res 6:153, 1982.
Jacobs, S. Pathologic Grief. American Psychiatric Press, Washington, DC, 1993.
Jahanshahi, M., C. D. Marsden. Depression in torticollis: a controlled study. Psychol Med 18:925, 1988.
Jahanshahi, M., C. D. Marsden. Psychological functioning before and after treatment of torticollis with botulinum toxin. J Neurol Neurosurg Psychiatry 55:229, 1992.
Jellinger, K. A. Post mortem studies in Parkinson's disease—is it possible to determine brain areas for specific symptoms? J Neural Transm Suppl 56:1, 1999.
Jenike, M. A., L., Baer H. T., Ballantine et al. Cingulotomy for refractory obsessive-compulsive disorder. Arch Gen Psychiatry 48:548, 1991.
Johnson, W. G. Late-onset neurodegenerative diseases—the role of protein insolubility. J Anat 196(Pt 4):609, 2000.
Juncos, J. L., G. Fabbrini, M. M. Mouradian, et al. Dietary influences on the antiparkinsonian response to levodopa. Arch Neurol 44:1003, 1987.
Junque, C., M. Alegret, F. A. Nobbe, et al. Cognitive and behavioral changes after unilateral posterventral pallidotomy: relations with lesional data from MRI. Mov Disord 14:780, 1999.
Kanazawa, I., M. Murata, M. Kimura. Roles of dopamine and its receptors in generation of choreic movements. Adv Neurol 60:107, 1993.
Kang, U. J., R. E. Burke, S. Fahn. Natural history and treatment of tardive dystonia. Move Dis 1: 193, 1986.
Kane, J. M., M. Woerner, M. Borenstein, et al. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull22(1):254, 1986.
Karstaedt, P. J., J. H. Pincus. Protein redistribution diet remains effective in patients with fluctuating parkinsonism. Arch Neurol 49:149, 1992.
Kayton, W. Major depression and chronic medical illness. Sem Clin Neuropsychiatry 3:81, 1998.
Kaufman, J. P. Plotsky, C. Nemeroff, et al. Effects of early adverse experience on brain structure and function. Biol Psychiatry 48:778, 2000.
P.223
Klatka, L., E. Louis, R. Schiffer. Psychiatric features of Lewy Body dementia, Neurology 47:1148, 1996.
Klawans, H. L., Jr. A pharmacologic analysis of Huntington's chorea. Eur Neurol 4:148, 1970.
Klawans, H. L., R. Rubovits. Central cholinergic-anticholinergic antagonism in Huntington's chorea. Neurology 2 2:107, 1972.
Klawans, H. L., A. Barr. Prevalence of spontaneous lingual-facial-buccal dyskinesia in the elderly. Neurology 32:558, 1982.
Klonoff, H., C., Clark, J. Oger, et al. Neuropsychological performance in patients with mild multiple sclerosis. J Nerv Ment Dis179(3):127, 1990.
Kohn, Y., J. Zislin, O. Agid, et al. Increased prevalence of negative life events in subtypes of major depressive disorder. Comp Psychiatry42:57, 2001.
Koller, W. C. Edentulous orodyskinesia. Ann Neurol 13:97, 1983.
Kornhuber, J., G. Quack, W. Danysz, et al. Therapeutic brain concentration of the NMDA receptor antagonist amantadine.Neuropharmacology 34:713, 1995.
Koshino, Y., Y. Wada, K. Isaki, Kurat. A long-term outcome of tardive dyskinesia in patients on antipsychotic medication. Clin Neuropharmacol 14(6):537, 1991.
Kupfer, D. J., M. E. Thase. The use of the sleep laboratory in the diagnosis of affective disorder. Psychiatr Clin N Am 5:3, 1983.
Kurlan, R., E., Caine, A. Rubin, et al. Cerebrospinal fluid correlates of depression in Huntington's disease. Arch Neurol 45:881, 1988.
Kurlan, R. Tourette's syndrome and “PANDAS”: will the relation bear out? Neurology 50:1530, 1998.
Kuzis, G., L., Sabe, Tiberti, et al. Cognitive functions in major depression and Parkinson. Arch Neurol 54:982, 1997.
Lachenmayer, L. Parkinson's disease and the ability to drive. J Neurol 247 (suppl 4): 28, 2000.
Landau, W. M. Clinical neuromythology IX. Pyramid sale in the bucket shop: DATATOP bottoms out. Neurology 40:1337, 1990.
Lauterbach, E. C., J. G., Jackson, S. T. Price, et al. Clinical, motor, and biological correlates of depressive disorders after focal subcortical lesions. J Neuropsychiatry Clin Neurosci 9:259, 1997.
Leenders, K. L., A. J., Palmer, N. Quinn, et al Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry 49:853, 1986a.
Leenders, K. I., W. H. Poewe, A. J., Palmer, et al Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated positron emission tomography. Ann Neurol 20:258, 1986b.
Lees, A. J. The concept of bradyphrenia Rev Neurologique 150:823, 1994.
Lewy, A. J., T. A. Wehr, F. K. Goodwin, et al. Manic-depressive patients may be sensitive to light. Lancet 1: 383, 1982a.
Lewy, A. J., T. A. Wehr, N. E. Rosenthal et al. Melatonin secretion as a neurobiological marker and effects of light in humans.Psychopharmacol Bull 18:127, 1982b.
Lieberman, A., Managing the neuropsychiatric symptoms of Parkinson's disease. Neurology 50(Suppl 6):S33–S38, 1998.
Loosen, P. T., A. J. Prange. Serum thyrotropin response to thyrotropin releasing hormone in psychiatric patients: a review. Am J Psychiatry 139:405, 1982.
P.224
Lorenzo, A., M. Yuan, Z. Zhang, et al. Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nat Neurosci 3:460, 2000.
Lupien, S. J., M. deLeon, DeSanti, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1:69, 1998.
Maes, M., H. Meltzer. The serotonin hypothesis of major depression. In Psychopharmacology, F. Bloom, D. Kupfer, eds. Raven Press, New York, 1995, pp. 933–944.
Mann, J., V. Arango. Abnormalities of brain structure and function in mood disorders. In: Neurobiology of Mental Illness, D. Charney, E. Nestler, B. Bunney, eds. Oxford University Press, New York, 1999, pp. 385
Maras, K., L. Clark, W. Katon, et al. Mixed anxiety-depression. DSM IV Sourcebook. American Psychiatric Press, Washington, DC, 1996, p. 623.
Marder, K., M. X. Tang, L. Cote, et al. The frequency and associated risk factors for dementia in patients with Parkinson's disease. Arch Neurol 52:695, 1995.
Maricle, R. A., J. G. Nutt, R. J. Valentine, J. H. Carter. Dose-response relationship of levodopa with mood and anxiety in fluctuating Parkinson's disease: a double-blind, placebo-controlled study. Neurology 45:1757, 1995.
Martinez-Martin, P., C. F. O'Brien. Extending levodopa action: COMT inhibition. Neurology 50(Suppl 6):S27–S32, 1998.
McAllister, T. Pseudodementia. Am J Psychiatry 140:52:81, 1983.
McEwen, B. S. Protective and damaging effects of stress mediators, N Engl J Med 338:171, 1998.
McHugh, P. R. The neuropsychiatry of basal ganglia disorders: a triadic syndrome and its explanation. Neuropsychiatry, Neuropsychol Behav Neuro 2:239-247, 1989.
McKinney, W. Stress adaption and affective disorders. Sem Clin Neuropsychiatry 6:1, 2001.
Melamed, E., F. Hefti, R. J. Wurtman. Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in parkinsonism. Ann Neurol8:558, 1980.
Mena, I., G. C. Cotzias. Protein intake and treatment of Parkinson's disease with levodopa. N Engl J Med 292:181, 1975.
Mendez, M. F. Huntington's disease: update and review of neuropsychiatric aspects. Intl J Psychiatry Med 24:189, 1994.
Menza, M. A., L. I. Golbe, R. A. Cody, et al. Dopamine-related personality traits in Parkinson's disease. Neurology 43:505, 1993. a
Menza, M. A., D. E. Robertson-Hoffman, A. S. Bonapace. Parkinson's disease and anxiety: comorbidity with depression. Biol Psychiatry34:465, 1993. b
Menza M. A., M. H. Mark, D. J. Burn, Brooks. Personality correlates of [18F] dopa striatal uptake: results of positron-emission tomography in Parkinson's disease. J Neuropsychiatry Clini Neurosci 7:176, 1995.
Merikangas, K., D. Kupfer. Mood disorders: genetic aspects. In: Comprehensive Textbook of Psychiatry/VI, H. Kaplan, B. Sadock, eds. Williams and Wilkins, Baltimore, 1995, pp. 1102.
Metman, L. V, P. Del Dotto, P. van den Munckhof Fang, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 50:1323, 1998.
Metman, C. V, P. Del Dotto K. LePoole, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol56:1383, 1999.
Miller, H., P. Delgado, R. Salomon, et al. Effects of alpha-mehyl-paratyrosine (AMPT) in drug-free depressed patients.Neuropsychopharmacol 14:151, 1996.
P.225
Mouradian, M. M., I. J. Heuser, F. Baronti, et al. Pathogenesis of dyskinesias in Parkinson's disease Ann Neurol 25:523, 1989.
Mouradian, M. M., J. L. Juncos, G. Fabbrini, et al. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part II. Ann Neurol 24:372, 1988.
Murphy, D. L., H. K. Brodie, F. K. Goodwin. Regular induction of hypomania by L-DOPA in “bipolar” manic-depressive patients. Nature229:135, 1971.
Nauseida, P. A., L. A. Bieliauskas, L. D. Bacon, et al. Chronic dopaminergic sensitivity after Sydenbam's chorea. Neurology 33:750, 1983.
Nemeroff, C, Evans, D. Correlation between the dexamethasone suppression test in depressed patients and clinical response. Am J Psychiatry 141:247, 1984.
Nemeroff, C., L. DeVane, B. Pollock. Newer antidepressants and the cytochrome P450 system, Am J Psychiatry 153:311, 1996.
Newport, J., C. Nemeroff. Childhood trauma: psychiatric and neurobiologic consequences. Sem Clin Neuropsychiatry (7), 2002.
Nibuya, M., S. Morinobu, R. Duman. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatment. J Neurosci 15: 7539, 1995.
Nibuya, M., E. J. Nestler, R. S. Duman. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16: 2365, 1996.
Nofzinger, E., M. Keshavan, D. Buysse, et al. The neurobiology of sleep in relation to mental Illness. In: Neurobiology of Mental Illness, D. Charney, E. Nestler, B. Bunney, eds. Oxford University Press, New York, 1999, pp. 915.
Nyenhuis, D. L., S. M. Rao, J. M. Zajecka, et al. Mood disturbance versus other symptoms of depression in multiple sclerosis. JINS 1:291, 1995.
Nutt, J. G., W. R. Woodward, P. Hammerstad, et al The “on-off” phenomenon in Parkinson's disease, relation to levodopa absorption and transport.N Engl J Med 23;310, 1984.
Olanow, C. W., P. Jenner, D. Brooks. Dopamine agonists and neuroprotection in Parkinson's disease. Ann Neurol 44(3 Suppl 1):S167, 1998.
Olanow, R. Watts, W. Koller. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines.Neurology 56 (Suppl 5): S1, 2001.
Olanow, T. Freeman, J. Kordowes. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 345:146, 2001.
Parkinsonism Study Group. Pramipexole vs levodopa as initial treatment for parkinson disease: a randomized controlled trial. JAMA284:1931, 2000.
Phillips, K., M. Dwight, S. McElroy, Efficacy and safety of fluvoxamine in body dysmorphic disorder. J Clin Psychiatry 59:165, 1998.
Piggott, T., S. Seay. A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder. J Clin Psychiatry60:101, 1999.
Pincus, J. H., K. M. Barry. Dietary method for reducing fluctuations in Parkinson's disease. Yale J Biol Med 60:133, 1987.
Pincus, J. H., Plasma levels of amino acids correlate with motor fluctuations in parkinsonism. Arch Neurol 44:1006, 1987.
Pincus, J. H., Influence of dietary protein on motor fluctuations in Parkinson's disease. Arch Neurol 44:270, 1987.
Pincus, J. H., Protein redistribution diet restores motor function in patients with doparesistant “off” periods. Neurology 38:481, 1988.
P.226
Post, R., S. R. Weiss. A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures. Mol Neurobiol. 13:33, 1996.
Price, D. L., S. S. Sisadia, R. Borchelt. Genetic neurodegenerative diseases: the human illness and transgenic models. Science 282:1079, 1998.
Rabey, J. M., T. A. Treves, M. Y. Neufeld, et al. Low-dose clozapine in the treatment of levodopa-induced mental disturbances in Parkinsion's disease. Neurology 45:432, 1995.
Rajput, A. H., R. Pahwa, P. Pahwa, Rajput. Prognostic significance of the onset mode in parkinsonism. Neurology 3:829, 1993.
Ramasubbu, R. A. Ravindran, Y. Lapierre. Serotonin and dopamine in obsessive-compulsive disorder. Phamacopsychiatry 33:236, 2000.
Rapoport, J. L., D. H. Ryland, M. Kriete. Drug treatment of canine acral lick: an animal model of obsessive-compulsive disorder. Arch Gen Psychiatry 49:517, 1992.
Rascol, O., D. J. Brooks, A. D. Korczyn, et al. A five-year study of the incidence dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 342:1484, 2000.
Rauch, S. Neuroimaging research and the neruobilogy of obsessive compulsive disorder. Biol Psychiatry 47:174, 2000.
Riley, D., A. E. Lang. Practical application of a low-protein diet for Parkinson's disease. Neurology 38:1026, 1988.
Robinson, D., H. Wu, R. A. Munne, et al. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch Gen Psychiatry 52:393, 1995.
Romeo, E., et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 155:910, 1998.
Sacher, E. J. Corticosteroids in depressive illness. Arch Gen Psychiatry 17:544, 1967.
Sadovnick, A. D., R. A. Remick, J. Allen, et al. Depression and multiple sclerosis. Neurology 46:628–632, 1996.
Sage, J. I, M. H. Mark. Basic mechanisms of motor fluctuations. Neurology 44 (Suppl 6):S10, 1994.
Sage, H., S. Trooskin, P. K. Somalia, et al. Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson's disease. Neurology 39(Suppl 2): 60, 1989.
Sage, J. I., M. H. Mark. Basic mechanisms of motor fluctuations. Neurology 44 (7Suppl 6):S10, 1994.
Sajatovic, M., L. Ramirez. Clozapine therapy in patients with neurologic illness. Intl J Psychiatry Med 25(4):331, 1995.
Sakamoto, K., S. Nakadaira, K. Kamo, et al. A longitudinal follow-up study of seasonal affective disorder. Am J Psychiatry 152:862, 1995.
Sanchez-Ramos, J. R., R. Ortoll, G. W. Paulson. Visual hallucinations associated with Parkinson disease. Arch Neurol 53:1265, 1996.
Sanders, A., S. Detera-Woodleigh, E. Gershon. Molecular genetics of mood disorders, In: Neurobiology of Mental Illness D. Charney, E. Nestler, B. Bunney, eds. Oxford University Press, New York, 1999.
Schatzberg, A., J. Schildkraut. Recent studies on norepinephrine systems in mood disorders. In: Psychopharmacology, F. Bloom, D. Kupfer, eds. Raven Press, New York, 1995.
Schatzberg, A., C. Nemeroff. APPI Textbook of Psychopharmacology, 2nd Edition, American Psychiatic Press, Washington DC, 1998.
P.227
Schwartz, P., C. Brown, T. Wher, et al. Winter seasonal affective disorder. Am J Psychiatry 153:1028, 1996.
Seeman, P., H. H. Van Tol. Dopamine receptor pharmacology. Trends Pharmacol Sci 15:264, 1994.
Shannon, K. M., R. D. Penn, J. S. Croin, et. al. Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients. Neurology 50:434, 1998.
Sharma, A. K., M. Behari, G. K. Ahuja. Clinical and demographic features of Meige's syndrome. J Assoc Phy Ind. 44:645, 1996.
Smith, K., G. Fairburn, P. Cowen. Relapse of depression after rapid depletion tryptophan, Lancet 349:915–919, 1997.
Sobin, C., H. A. Sackeim. Psychomotor symptoms of depression. Am J Psychiatry 154:4, 1997.
Spars, J. E., R. Grener. Does the dexametbasone suppression test distinguish dementia from depression? Am J Psychiatry. 139:238, 1982.
Spencer, S. E., G. F. Wooten. Altered pharmacokinetics of L-dopa metabolism in rat striaturn deprived of dopaminergic innervation.Neurology 34:1105, 1984.
Spillantini, M. G., M. Goedert. The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Ann NY Acad Sci 920: 16, 2000.
Stahl, S. Selecting an antidepressant by using mechanism of action to enhance efficacy and avoid side effects. J din Psychiatry 59(Suppl 18):23, 1998.
Stein, M. B., I. J. Heuser, J. L. Juncos, et al. Anxiety disorders in patients with Parkinson's disease. Am J Psychiatry 147 2:217, 1990.
Stern, Y, K. Marder, M. X. Tang, R. Mayeux. Antecedent clinical features associated with dementia in Parkinson's disease. Neurology43:1690, 1993.
Stevens, J. R. Motor disorders in schizophrenia. Engl. J Med 290: 110, 1974.
Stibe, C. M., A. J. Lees, P. A. Kempster, et al Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1(8582):403, 1988.
Stine, O., J. Xu, R. Koskela, et al. Evidence for linkage of bipolar disorder to chromosome 18 with parent-of-origin effect. Am J Hum Genet 57:1384, 1995.
Straub, R., T. Lehner, Y. Luo, et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nat Genet8:291, 1994.
Sullivan, P., M. Neale, K. Kendler. Genetic epidemiology of major depression. Am J Psychiatry 157:1552, 2000.
Swedo, S. E., H. L. Leonard, B. B. Mittleman, et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with Rheumatic fever. Am J Psychiatry 154:110, 1997.
Tandberg, E., J. P. Larsen, D. Aarsland, K. Laake, J. L. Cummings, Risk factors for depression in Parkinson's disease, Arch Neurol 54:625, 1997.
Tandberg, E., J. P. Larsen, D. Aarsland, J. L. Cummings. The occurrence of Parkinson's disease. Arch Neurol 53:175, 1996.
Taylor, A. E., J. A. Saint-Cyr, E. Lang. Procedural learning and neostriatal dysfunction in man. Brain 111:941, 1988.
Taylor, A. E. Lang, J. A. Saint-Cyr, et al. Cognitive processes in idiopathic dystonia treated with high dose anticholinergic therapy: implications for treatment strategies din Neuropharm 14:62, 1991.
Thase, M. Treatment resistant depression. In: Psychopharmacology, F. Bloom, D. Kupfer, eds. Raven Press, New York, 1995, pp. 1081.
P.228
Tolosa, E. S. Clinical features of Meige's disease (idiopathic orofacial dystonia): a report of 17 cases. Arch Neurol 38:147, 1981.
Trendelenburg, U. Mechanisms of supersensitivity and subsensitivity to sympathornimetic amines. Pharmacol Rev 18:629, 1966.
Tsui, J. K., S. Ross, K. Poulin, et al. The effect of dietary protein on the efficacy L-dopa: a double-blind study. Neurology 39:549, 1989.
Tucker, G., P. Roy-Byrne, J. Fann, et al. Psychiatry for the neurologist. Continuum 3: 3, 1997.
Vandel, P., B. Bonin, E. Leveque, et al. Tricyclic antidepressant-induced extrapyramidal side effects. Eur Neuropsychopharmacol 7:207, 1997.
van Harten, P. N., H. W. Hoek, G. E. Matroos, et al. Intermittent neuroleptic treatment risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III. Am J Psychiatry 155(4):565, 1998.
Verhagen Metman, L. P. Del Dotto, P. van der Munckhof, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 50:1323, 1998.
Webb, M., P. T. Trzepacz. Huntington's disease: correlations of mental status with chorea. Biol Psychiatry 22:751, 1987.
Weiner, W. J. Is levodopa toxic? Arch Neurol 57:408, 2000.
Weissman, M. M. Cross-national epidemiology of obsessive-compulsive disorder. The Cross National Collaborative Group J Clin Psychiatry55(Suppl 3):5, 1994.
Wenzel, T. P. Schnider, A. Wimmer, et al. Psychiatric comorbidity in patients with spasmodic torticollis. J Psychosom Res 44: 687, 1998.
Whatmore, C. B., R. M. Ellis. Further neuropbysiologic aspects of depressed states. Arch Gen Psychiatry 6:243, 1962.
Whybrow, P, J. Mendels. Towards a biology of depression. Am J Psychiatry 125:1491, 1969.
Whybrow, P., H. S. Akiskal, W. T. McKinney, Mood Disorders, Plenum Press, New York, 1984.
Wiggins, S., P. Whyte, M. Huggins, et al. The psychological consequences of predictive testing for Huntington's disease. N Engl J Med327:1401, 1992.
Wilner, P. Dopaminergic mechanisms in depression and mania. In: Psychopharmacology, F. Bloom, D. Kupfer, eds. Raven Press, New York, 1995, pp. 921.
Wooten, G. F., Progress in understanding the pathophysiology of treatment-related fluctuations in Parkinson's disease. Ann Neurol24:363, 1988.
Wulsin, L., G. Vaillant, V. Wells. A systematic review of the mortality depression. Psychosom Med 61:6, 1999.
Zeman, W. Pathology of the torsion dystonias (dystonia musculorum deformans). Neurology 20:79, 1970.
Zung, W.K.K. A self-rating depression scale. Arch Gen Psychiatry 12:63, 1965.