ANXIETY DISORDERS
IN PARKINSON’S DISEASE: INSIGHTS
INTO THE NEUROBIOLOGY OF NEUROSIS
It is within living professional memory that mental states in clinical medicine were understood as radically demarcated from their underlying neuroanatomy, neurochemistry, and neuropsychology.
The behavioral disorders were relegated to the realm of the “functional,” whereas all the rest of clinical medicine was navigated to the “organic” subcontinents of neurology, cardiology, and general medicine. The bridging insights of neuropsychiatry over the past 20 years have greatly improved our insights about the interactive nature of neurology and psychiatry [1]. First in the aphasias, then in the dementias, and later in the affective disorders, neuropsychiatry has helped us to understand how thought, feeling, and action can be directly influenced by the neurobiology of certain neurologic diseases.
The anxiety disorders may be the most common of the psychiatric disorders [2].
Lifetime prevalence rates for DSM-III-R-diagnosable anxiety disorders are as high as 30.5% for women and 19.2% for men [3]. These disorders occur across the lifespan, from childhood to later years. They include a variety of distressing symptoms including nervousness, sleeplessness, hypochondrias is, and many somatic symptoms.
They tend to persist, and they are difficult to diagnose and treat. One might wonder whether these disorders will become the mood disorders of the next century.
The observation that persons suffering from certain neurological diseases develop certain behavioral syndromes at incidence rates greater than expected has been a most useful insight for neuropsychiatry. Such observations have substantially shaped our theoretical understanding of the affective disorders [4], obsessive–compulsive disorder [5], and the psychoses [6].
The anxiety disorders, however, have not received analogous clinical neuropsychiatric investigation. We do have certain neurobiological insights concerning the neuroanatomy and neurochemistry which is of importance to the clinical expression of generalized or episodic anxiety [7]; however, these insights derive primarily from animal experiments, or from functional imaging in humans. Disease-based neuropsychiatry has yet to make its contributions to our understanding of the anxiety disorders.
Clinical reports are now becoming available which indicate that there might be an association between the anxiety disorders and idiopathic Parkinson’s disease (PD), or its treatments [8]. Both episodic and generalized anxiety syndromes have been reported to occur in PD populations at elevated rates compared with normal and disease controls [9–11]. Some of these patients clearly seem to have onset of the anxiety symptomatology prior to first motor symptoms of PD, suggesting some underlying, shared neurobiologic vulnerability to PD and anxiety [12]. It has been difficult to specify a relationship between episodic or generalized anxiety in PD patients and dopamine agonist pharmacotherapy. Some investigators have reported an association between the timing of levodopa dosing and panic attacks [13], but others have not [9]. In one study of levodopa infusions under controlled conditions anxiety was reduced in patients with advanced PD and motor fluctuations [14]. It is certainly the case, however, that older neurologists recall remarkable anxiety symptoms in PD patients prior to the advent of levodopa therapy, and that many PD patients demonstrate their anxiety symptoms prior to the initiation of levodopa [15].
It is not difficult for us to conceptualize neuroanatomic structural circuits that might subserve the reported clinical link between anxiety disorders and extra pyramidal movement disorders. From the work of Mogenson and colleagues in the 1970s the nucleus accumbens has been described as an interactive neural relay, modulating striate motor system output by ventral tegmental and temporal lobe limbic inputs [16]. The shell of the accumbens is closely linked to or continuous with the anterior extension of the amygdale [17]. Together, these structures provide circuitry linkage between the extrapyramidal motor system and limbic structures, which are activated in stress response, reward, and fear [18, 19]. Brain imaging studies in a few psychiatric patients with anxiety have noted temporal lobe and basal ganglion metabolic
changes [20, 21].
Similarly, we already have sufficient understanding of the neurochemistry underlying fear and anxiety to contemplate a shared vulnerability with the neurochemical deficits of PD. The locus ceruleus-based norepinephrine system in the brainstem almost certainly has an important role in the processing of fear-related stimuli [7].
Electrical stimulation of the locus produces fear behaviors in monkeys [22]. When cats are exposed to threatening situations cellular electrode studies indicate that locus ceruleus neurons increase their firing [23]. Abnormal regulation of presynaptic a2-adrenergic receptors has been described from evidence related to pharmacologic probes in panic disorder [24]. The loss of noradrenergic locus ceruleus neurons has been described in PD, in addition to the dopamine-related cell loss in the substantia nigra [25]. Our group has reported an unusual susceptibility of some PD patients to yohimbine-induced panic attacks [26]. Yohimbine is an a2-adrenergic antagonist that is capable of generating a simulated panic attack in vulnerable individuals.
The challenge for neuropsychiatry deriving from these observations is twofold.
First, we need to better understand the generalizability of the anxiety symptoms of PD to generalized anxiety, phobic disorders, and panic disorder in the population at large. To what extent are the phenomenologies of the disorders similar, and to what extent are they different? What is the natural history of the anxiety disorder associated with PD? Second, we can use this potential neurologic model for panic/anxiety to help us understand better the underlying neurobiology of panic and anxiety. Is there evidence of neurochemical or neurophysiologic vulnerability to panic/anxiety in the newly diagnosed PD patient? What do the pharmacological and surgical therapies for PD do to locus ceruleus firing rates? Do the new therapies for PD
affect the neurobehavioral disorder associated with the movement disorder? An entire horizon of clinical neuropsychiatric investigation awaits us.