Anxiety

♦ Anxiety disorders are classified into the following: panic disorder without agoraphobia; panic disorder with agoraphobia; agoraphobia without panic disorder; specific phobia; social phobia; obsessive-compulsive disorder (OCD); post-traumatic stress disorder; acute stress disorder; generalized anxiety disorder (GAD); anxiety disorder due to a general medical condition; substance-induced anxiety disorder; and anxiety disorder not otherwise specified.

O A panic attack is a discrete period of a sudden onset of intense apprehension, fear-fulness, or terror, often associated with feelings of impending doom. During these attacks, symptoms such as shortness of breath, palpitations, chest pain, choking or smothering sensations, and fear of 'going crazy' or losing control are present. In panic disorder, there is a persistent concern over recurrent unexpected panic attacks.

Antidepressants

DRUG

DOSE (mg/d)

SEDATION

HYPOTENSION

ANTIMUSCARINIC EFFECTS

SEXUAL DYSFUNCTION

Fluoxetine

l0—80

Negligible

Negligible

Negligible

Considerable

Mild

Fluvoxamine

50-300

Negligible

Negligible

Negligible

Moderate

Moderate

Paroxetine

20-50

Mild

Negligible

Mild

Severe

Moderate

Sertraline

25-l00

Negligible

Negligible

Negligible

Moderate

Mild

Citalopram

l0-60

Mild

Negligible

Mild

Moderate

Mild

Escitalopram

l0-20

Mild

Negligible

Mild

Moderate

Mild

Nefazodone

300-600

Moderate

Moderate

Negligible

Mild

Amitriptyline 25-200 Considerable Moderate Considerable Mild Considerable <u

Doxepin 75-150 Moderate Moderate Considerable Mild Moderate jj'S

Imipramine 50-200 Moderate Considerable Moderate Mild Moderate otins

TCAs

Amitriptyline 25-200 Considerable Moderate Considerable Mild Considerable <u

Doxepin 75-150 Moderate Moderate Considerable Mild Moderate jj'S

Imipramine 50-200 Moderate Considerable Moderate Mild Moderate otins

Desipramine 100-300 Mild Mild Mild Negligible Mild

Nortriptyline 50-150 Mild Mild Mild SNRIs

Venlafaxine 75-375 Mild Negligible Mild

Mirtazapine 15-45 Moderate Moderate Mild Moderate Considerable

OTHER

Bupropion 150-450 Negligible Negligible Mild Negligible Negligible

Negligible Mild

Considerable Mild

76 Antidepressants. Side-effects of SSRIs and TCAs used in the treatment of depression in PD.

O Agoraphobia is anxiety about, or avoidance of, places or situations from which escape might be difficult (or embarrassing).

O In specific phobia, the anxiety is provoked by exposure to a specific feared object or situation, often leading to avoidance behaviour, while social phobia is provoked by exposure to certain types of social or performance situations.

O OCD is characterized by obsessions (which cause marked anxiety or distress) and/or by compulsions (which serve to neutralize anxiety).

O Posttraumatic stress disorder is characterized by the re-experiencing of an extremely traumatic event accompanied by symptoms of increased arousal and by avoidance of stimuli associated with the trauma. The symptoms are similar to those of acute stress disorder, but they occur immediately in the aftermath of an extremely traumatic event. O GAD is characterized by at least 6 months of persistent anxiety and worry.

♦ Most non-PD studies in the elderly have shown that anxiety disorders are less common than in younger adults. In contrast, anxiety disorders in PD have been found to exceed prevalence rates in the geriatric population, and occurred more frequently than in any other medical illness of comparable disability.

The onset of anxiety in late age in PD, and its higher prevalence compared to the geriatric population and other chronic illnesses, is suggestive that anxiety may be aetiologically related to the neurobiological changes that accompany PD and is not simply a behavioural reaction to chronic disability.

GAD, panic disorder, social phobia, phobic disorder, agoraphobia, and OCD have all been described with PD.

Most studies found no significant difference in PD severity between those with and those without anxiety. Symptoms like panic, flushing, and sweating can be principal nonmotor manifestations during the 'off state. Moreover, pervading anxiety disorders are reported to occur more often among PD patients who experience 'on'/'off motor fluctuations and symptoms tend to worsen during the 'off' state. Thus, anxiety itself can be a manifestation of an 'off state, or can be worsened by motor fluctuations, or can occur independently of, and even precede, motor manifestations. Relationship to depression and dementia: O One study found that 92% of PD patients with anxiety also had depression and 67% of depressed PD patients carried a diagnosis of anxiety.

O Another study found depression in combination with panic and/or anxiety occurred more commonly among PD patients compared to healthy spouse controls. O While two studies hypothesized that anxiety may be less among demented PD patients, others have found no relationship between the two disorders. Neurobiology of anxiety in PD: O Anxiety in PD may be directly related to dopaminergic deficit or can be the result of imbalance in other neurochemical pathways. O The main neurotransmitters implicated in the pathogenesis of anxiety are norepinephrine (NE), serotonin, gamma-aminobutyric acid (GABA), as well as some neuropeptides. O PET studies in GAD demonstrated decreased glucose metabolism in basal ganglia. A clinical study demonstrated a strong correlation of anxiety to left body parkinsonism. The same correlation was evident for depressive symptoms.

♦ Treatment. The key to successful management of anxiety in PD is its early recognition. A 'team approach' to treatment is most beneficial. O Nonpharmacological management, that includes education, counselling, and stress-reduction strategies, should be an integral part of treatment. O Studies on the pharmacological management of anxiety in PD are wanting. PD motor symptoms need to be adequately treated. Although most studies find no correlation between PD disability and incidence of anxiety, for the subset of patients with motor fluctuations, there is a clear correlation of anxiety with the 'off states. O Benzodiazepines. The majority of PD

patients with anxiety will require anxiolytic therapy in addition to dopaminergic medications. Benzodiazepines can be effective for management of GAD, panic disorders, social phobias, but are not effective in OCD. There is no adverse interaction between benzodi-azepines and dopaminergic therapy but the potential additive sedative effect of both agents can lead to escalation of daytime somnolence, disruption of sleep-wake cycle, and falling. Cognitively impaired patients can have worsening of their cognition and are at risk for hallucinations. These agents should be avoided in the elderly. O SSRIs. These are becoming the preferred agents for management of essentially any type of anxiety. SSRIs have a favourable side-effect profile and limited drug-drug interactions. They are widely used in PD for relief of depression and associated anxiety. O Concomitant use of SSRIs and MAOB-Is can lead to the development of 'serotonin syndrome' (SS). Non-selective MAOB-Is are contraindicated in patients taking levodopa due to the risk of hypertensive crisis. Selegiline is a selective MAOB-I and does not have monoamine oxidase-A inhibitory effect at the prescribed doses below 10 mg/day. However, at higher doses it becomes a non-selective monoamine oxidase inhibitor. The selegiline package insert has a warning against the concomitant use of either TCAs or SSRIs due to the potential CNS toxicity such as SS, presenting with alterations of mental status, motor and autonomic dysfunction. Despite the theoretical concern for increased risk of SS with concomitant use of selegiline and antidepressants, it is a rare phenomenon based on the manufacturer's information and survey of a large group of movement disorder specialists.

O There are case reports of motor worsening or new-onset drug-induced parkinsonism in the setting of SSRI use, specifically fluoxetine. O TCAs act by blocking noradrenaline and serotonin uptake as well as producing long-term increase in their receptor sensitivity. There is a role for TCAs in the management of PD-related pain and sleep dysfunction, as well as hypersalivation. However, their use in PD is limited by their anticholinergic side-effects. TCAs carry a high risk of causing or worsening confusion. O Bupropion is a monocyclic antidepressant with indirect DA properties. The most concerning side-effect of the drug is seizures. Its effect on PD anxiety has not been systematically evaluated but its overall 'stimulating' properties may limit its use. O Buspirone, which pharmacologically is related to bupropion, also has DA properties. It can be effective for GAD, but is less likely to help panic or social phobia. In PD, the drug was well tolerated in doses up to 60 mg/day but did not produce either antiparkinsonian or anxiolytic effect. At higher doses (100 mg/day) it caused worsening of motor function and worsening of anxiety.

O Mirtazapine is a newer antidepressant which acts via indirect enhancement of serotonin 5-HT1 receptors as well as direct inhibition of alpha-2 presynaptic adrenergic receptors. Shown to be effective in GAD, it could potentially be a good treatment option for PD patients with anxiety and sleep dysfunction due to its sedative effect at low doses.

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