What it is:A slowly progressive neurodegenerative disease where dopamine-producing neurons in the substantia nigra pars compacta die off, taking the striatum's dopamine supply with them. Second most common neurodegenerative disorder after Alzheimer's, mean age of onset around 60.
The core problem:By the time symptoms show up, a patient has already lost 70-80% of their striatal dopamine. That dopamine normally keeps the basal ganglia's "go" and "stop" circuits balanced. Take it away and the net effect is too much inhibition of the thalamus, so the motor cortex can't get the green light it needs. The patient becomes slow, stiff, and shaky, not because muscles are weak, but because the signal to move smoothly never arrives.
What you do about it:Nothing available today slows or reverses the neurodegeneration. Every drug in this chapter is symptomatic: replace dopamine, mimic it, protect it from being broken down, or dampen the neurotransmitters that go unopposed once dopamine is gone. Pick the first agent based on the patient's age and how much functional impairment they have, then layer on more classes as dopamine reserve keeps shrinking.
Every class in this chapter maps onto exactly one of four strategies: replace dopamine (levodopa), mimic dopamine (agonists), protect dopamine from breakdown (MAO-B and COMT inhibitors), or hit a different target entirely (anticholinergics, amantadine, adenosine antagonism). If you can name which bucket a drug falls into, you already know roughly what it does and why it's used adjunctively versus first-line.
Two neuropathologic hallmarks define PD, both centered on the substantia nigra pars compacta (SNc): loss of the dopaminergic neurons that project to the striatum (caudate and putamen), and the appearance of Lewy bodies, intracytoplasmic inclusions built from misfolded alpha-synuclein. The degree of nigrostriatal dopamine loss tracks directly with motor severity, so this isn't a subtle biochemical shift, it's a near-total collapse of one neurotransmitter system in one specific pathway.
The basal ganglia normally regulate movement through two competing circuits running from the striatum to the thalamus and back to the motor cortex. The direct pathway(dopamine acting on D1 receptors) facilitates movement. The indirect pathway(dopamine acting on D2 receptors) normally restrains movement, and dopamine loss removes that restraint's counterbalance, tipping the whole circuit toward net inhibition of the thalamus. Clinical improvement seems to depend more on restoring D2 activity than D1, which is part of why D2/D3-selective dopamine agonists work as monotherapy.
Adenosine A2A receptors sit on the GABAergic neurons of the indirect pathway and normally oppose D2 signaling. That's the entire rationale for istradefylline: block A2A, and you prolong dopaminergic action on the same circuit without touching a dopamine receptor at all. It's the only nondopaminergic mechanism in this chapter aimed squarely at the direct/indirect pathway model.
Etiology is still unknown for the majority of patients (sporadic/idiopathic PD). Two genes, alpha-synuclein and LRRK2, link sporadic and familial disease, and mutations in PARKIN and PINK1 are associated with early-onset PD (before age 45). An environmental hypothesis (pesticide and toxin exposure, e.g. manganese, organophosphates) also has support. Practically, none of this changes first-line pharmacotherapy, but it explains why some young-onset patients get genetic counseling and why occupational history matters on intake.
Dopamine receptor blockers (antipsychotics, metoclopramide, prochlorperazine) can produce a clinical picture that mimics PD without the underlying Lewy body pathology. These cases tend to be symmetric, have less resting tremor, and don't respond to levodopathe way true PD does, three features that help distinguish it from idiopathic disease when you're taking a medication history.
PD develops insidiously and progresses over many years. Two mnemonics from lecture cover essentially everything you need: TRAPfor the motor core, SOAPfor everything else. Symptoms are classically asymmetric/unilateralat onset, a feature that itself helps distinguish PD from its mimics.
| T R A P - motor core | What it looks like |
|---|---|
| Tremor at rest | Rhythmic, ~3 cycles/sec, classic "pill-rolling" in the hands. Present in only about two-thirds of patients at diagnosis, and some never develop it, so its absence doesn't rule out PD. |
| Rigidity | Cogwheel or ratchet-like increased muscle tone. |
| Akinesia/Bradykinesia | Slowness or loss of voluntary movement. This is the one symptom that's mandatoryfor diagnosis, and its severity tracks loss of dopamine terminals. |
| Postural instability | Impaired balance, festinating gait (progressively quickening, shuffling steps), frequent falls. Tends to appear later than the other three. |
Other motor findings worth recognizing: decreased manual dexterity, diminished arm swing while walking, dysarthria and hypophonia (soft, slurred speech), dysphagia, "freezing" at movement initiation, hypomimia (masked, flat face), and micrographia (progressively smaller handwriting).
| S O A P - non-motor | Examples |
|---|---|
| Sleep disturbances | Insomnia, excessive daytime sleepiness, obstructive sleep apnea, REM sleep behavior disorder (acting out dreams, calling out, reaching, kicking) |
| Other | Anosmia (loss of smell, often predates motor symptoms by years), fatigue, speech changes, nausea |
| Autonomic | Constipation, sialorrhea (drooling), urinary problems, orthostatic hypotension, sexual dysfunction, diaphoresis, seborrhea, paroxysmal flushing |
| Psychological | Anxiety, depression, apathy, bradyphrenia (slowed thinking), cognitive impairment, hallucinosis/psychosis |
Bradykinesia is the one non-negotiable finding. Diagnostic criteria require bradykinesia PLUS at least oneof tremor, rigidity, or postural instability, not all four. Students who memorize TRAP as "need all 4" miss patients who never develop a tremor.
Anosmia, constipation, REM sleep behavior disorder, and depression can precede the motor diagnosis by years. Worth knowing because a patient describing this constellation without tremor yet is still worth watching closely.
PD is a clinical diagnosis. There is no blood test or genetic panel that confirms it, and imaging is used mainly to rule other things out, not to rule PD in.
| Step | Requirement |
|---|---|
| 1 | Bradykinesia plus at least oneof resting tremor, rigidity, or postural instability |
| 2 | Exclude other parkinsonism or tremor disorders |
| 3 | At least 3 supportive positive features: asymmetric onset, unilateral onset, progressive course, resting tremor, excellent response to carbidopa/levodopa, levodopa response sustained ≥5 years, presence of levodopa-induced dyskinesias |
It's counterintuitive, but "responds well to carbidopa/levodopa" is one of the supportive Step 3 criteria. Drug-induced parkinsonism and other mimics typically respond poorly, so a dramatic levodopa response actually helps confirm true PD retrospectively.
Goals of treatment:minimize symptoms, disability, and medication adverse effects while preserving quality of life. Patient/caregiver education, exercise, and nutrition are part of every regimen. No available treatment changes the disease course, so every decision is a symptom-control tradeoff, not a cure.
Exercise, physiotherapy, yoga, Tai Chi, and dance all improve symptoms, and the Lee Silverman Voice Treatment-BIGprogram has particular evidence behind it. This isn't a footnote, it's part of every regimen from diagnosis onward.
The handbook's algorithm splits initial drug choice by age 65and by which symptom dominates:
| Presentation | <65 years | ≥65 years |
|---|---|---|
| Tremor-predominant | Consider an anticholinergic | Carbidopa/levodopa |
| Bradykinesia, rigidity predominant | Dopamine agonist | Carbidopa/levodopa |
| Postural instability / gait impairment | Physical therapy | Physical therapy |
Dopamine agonists and anticholinergics carry real neuropsychiatric and orthostatic baggage that older adults tolerate poorly (confusion, hallucinations, falls). Carbidopa/levodopa is better tolerated in older or cognitively impaired patients, so age ≥65 essentially defaults straight to levodopa regardless of which symptom dominates. Younger patients get steered toward agonists or anticholinergics first specifically to delaylevodopa exposure, because motor complications are more common with younger age of onset and longer cumulative levodopa duration.
For patients with mild functional impairmentat any age, initial monotherapy often starts with a MAO-B inhibitor(usually rasagiline) instead, since it's well tolerated and has a low side-effect burden. Eventually, though, every PD patient ends up needing carbidopa/levodopa, either alone or combined with other agents, because it remains the single most effective drug for motor symptoms and no other class matches it once dopamine reserve keeps shrinking.
As motor fluctuations emerge, the response is to give carbidopa/levodopa more often or add a second class (COMT inhibitor, MAO-B inhibitor, adenosine antagonist, or dopamine agonist). If disabling dyskinesia or tremor persists despite an optimized regimen, deep brain stimulation (DBS)becomes an adjunct, not a replacement, for pharmacotherapy.
Bilateral, chronic, high-frequency electrical stimulation is the preferred surgical modality, most often targeting the subthalamic nucleus. It's reserved for patients with frequent motor fluctuations or disabling dyskinesia/tremor despite optimized medical therapy. A battery-powered neurostimulator (implanted like a pacemaker) delivers continuous stimulation; a neurologist adjusts voltage, frequency, and pulse width over time. The goal is often to allow lowermedication doses, which in turn reduces dyskinesia. Newer adaptive DBS (aDBS) self-adjusts stimulation based on the presence of medication, an evolution of the fixed-parameter systems used for over two decades.
Every drug class in PD pharmacotherapy fits one of these four buckets. Knowing which bucket a drug lives in tells you most of what you need to know about how it's used.
Levodopa is dopamine's immediate precursor, converted to dopamine once inside the CNS. Still the single most effective PD drug.
Dopamine agonists bind D2/D3 receptors directly, no enzymatic conversion and no need for a functional nigrostriatal pathway.
MAO-B inhibitors block central dopamine metabolism; COMT inhibitors block peripheral conversion of levodopa to dopamine, extending its half-life.
Anticholinergics rebalance acetylcholine left unopposed by dopamine loss. Amantadine boosts presynaptic dopamine release and blocks NMDA. Istradefylline blocks adenosine A2A on the indirect pathway.
Notice that only strategies 1 and 2 add dopaminergic tone directly; strategy 3 only works alongsidean existing dopamine source (there's nothing to protect from breakdown if there's no levodopa around, which is why COMT inhibitors are never monotherapy). Strategy 4 is the only bucket that doesn't touch the dopamine pathway directly at all.
All doses are mg/day unless noted. Carbidopa/levodopa doses are expressed as the levodopacomponent; the carbidopa/levodopa/entacapone combination is expressed as the entacaponecomponent.
| Medication | Starting Dose | Maintenance/Max Dose |
|---|---|---|
| Carbidopa/Levodopa products | ||
| Carbidopa/levodopa IR (Sinemet) | 300 mg/day† | 300-2000 mg/day† |
| Carbidopa/levodopa ODT (Parcopa) | 300 mg/day† | 300-2000 mg/day† |
| Carbidopa/levodopa CR | 400 mg/day† | 400-2000 mg/day† |
| Carbidopa/levodopa IR/ER (Rytary) | 435 mg/day† | 435-2450 mg/day† |
| Carbidopa/levodopa enteral suspension (Duopa) | 1000 mg/day† | 1000-2000 mg/day† |
| Carbidopa/levodopa/entacapone (Stalevo) | 600 mg/day‡ | 600-1600 mg/day‡ |
| Carbidopa alone | 25 mg/day | 25-75 mg/day |
| Levodopa alone | 84 mg/day | 84-420 mg/day |
| Dopamine agonists | ||
| Pramipexole | 0.125 mg/day | 1.5-4.5 mg/day |
| Pramipexole ER | 0.375 mg/day | 1.5-4.5 mg/day |
| Ropinirole | 0.75 mg/day | 9-24 mg/day |
| Ropinirole XL | 2 mg/day | 8-24 mg/day |
| Rotigotine (patch) | 2 mg/day | 2-8 mg/day |
| Bromocriptine | 2.5-5 mg/day | 15-40 mg/day |
| Apomorphine SQ (Apokyn) | 1-3 mg/day | 3-12 mg/day |
| Apomorphine SL film (Kynmobi) | 10 mg/dose | up to 30 mg/single dose |
| MAO-B inhibitors | ||
| Rasagiline | 0.5-1 mg/day | 0.5-1 mg/day |
| Safinamide | 50 mg/day | 50-100 mg/day |
| Selegiline | 5-10 mg/day | 5-10 mg/day |
| Selegiline ODT | 1.25 mg/day | 1.25-2.5 mg/day |
| COMT inhibitors (adjunct to levodopa only) | ||
| Entacapone | 200-600 mg/day | 200-1600 mg/day |
| Opicapone | 25-50 mg/day | 50 mg/day |
| Tolcapone | 300 mg/day | 300-600 mg/day |
| Anticholinergics | ||
| Benztropine | 0.5-1 mg/day | 1-6 mg/day |
| Trihexyphenidyl | 1-2 mg/day | 6-15 mg/day |
| Miscellaneous | ||
| Amantadine IR | 100 mg/day | 200-300 mg/day |
| Amantadine ER (Gocovri) | 137 mg/day | 274 mg/day |
| Amantadine ER (Osmolex) | 129 mg/day | 129-258 mg/day |
| Istradefylline | 20 mg/day | 20-40 mg/day§ |
†Expressed as levodopa component. ‡Expressed as entacapone component. §Use the 40 mg dose for patients who smoke >20 cigarettes/day (faster CYP1A1/3A4 clearance).
Mechanism:Levodopa is dopamine's immediate precursor. It crosses the blood-brain barrier (dopamine itself can't) and is converted to dopamine by L-amino acid decarboxylase (L-AAD) both centrally and peripherally. Carbidopa can't cross the BBB, so it stays in the periphery and blocks L-AAD there, which does two things at once: less peripheral dopamine means fewer GI/cardiovascular side effects, and more levodopa survives to actually reach the brain. About 75 mg/day of carbidopais usually enough to adequately block peripheral L-AAD, though some patients need more.
Formulations:IR (Sinemet), CR (Sinemet CR, ~70% bioavailable vs IR), ODT (Parcopa, for swallowing difficulty), IR/ER capsule (Rytary, ~75% bioavailable vs IR, can be swallowed whole or sprinkled on food), enteral suspension (Duopa, delivered via feeding tube pump for advanced disease), and an oral inhalation powder (Inbrija) used strictly as an add-on rescue for "off" episodes, never as a replacement for oral therapy.
Kinetics:Absorbed in the proximal duodenum via a saturable large neutral amino acid transporter, so high-protein meals compete for absorptionand can blunt effect; antacids promote gastric emptying and can speed absorption while meals in general delay it. Levodopa alone has an elimination half-life of about 1 hour; adding carbidopa extends it to ~1.5 hours, and adding a COMT inhibitor extends it further to ~2-2.5 hours. Time to peak: roughly 0.5-1 hour for IR, 1-4 hours for ER/CR.
Narrow-angle glaucoma. Concurrent nonselective MAO inhibitors, separate use by at least 14 days.
Adverse effects:nausea/vomiting (D2 activation at the chemoreceptor trigger zone; tolerance usually develops over months, manage with small doses and a nonprotein snack), orthostatic hypotension, cardiac arrhythmias, vivid dreams, dark/brownish urine discoloration, impulse control disorders (gambling, hypersexuality, overeating, excessive spending), and psychiatric effects (agitation, hallucinations, delusions, psychosis). No renal or hepatic dose adjustment is needed.
The tradeoff that defines this drug:it's the most effective agent available, and roughly 10% of patients per yeardevelop disabling motor complications on it, though these can also appear as early as 5-6 months after starting. Higher doses and younger age at PD onset both raise that risk, which is exactly why the algorithm tries to delay levodopa in younger patients when it can.
Mechanism:Direct D2/D3 receptor stimulation, no enzymatic conversion required and no dependence on a functioning nigrostriatal pathway, which is part of why they still work reasonably well even as neurons continue dying. The nonergot agents (pramipexole, ropinirole, rotigotine) are effective as monotherapy in mild-moderate PD and as adjuncts once motor fluctuations appear on levodopa, and they carry a lower risk of motor complicationsthan levodopa when used as first-line therapy.
Pramipexole:oral only, initial 0.125 mg TID titrated by 0.375 mg/day increments every 5-7 days, max 4.5 mg/day. Primarily renally excreted, dose adjustment needed for CrCl <50.
Ropinirole:oral only, initial 0.25 mg TID, titrated by 0.75-3 mg/day increments weekly, max 24 mg/day. Metabolized by CYP1A2, so fluoroquinolones and cigarette smoking can alter clearance. Dose adjustment for CrCl <30.
Rotigotine:the only transdermal option, once-daily patch providing continuous 24-hour delivery, 2-4 mg/day initial, up to 6-8 mg/day. No hepatic or renal dose adjustment. Rotate application sites every ~2 weeksto prevent skin reactions, and remove the patch before an MRI.
Apomorphine:the nonergot "rescue" agent for breakthrough "off" episodes in advanced PD, available as SQ injection or sublingual film. SQ triggers an "on" response within ~20 minutes lasting up to ~100 minutes; most patients need about 0.06 mg/kg. Premedicate with trimethobenzamidebefore initiation given severe nausea risk, and it's contraindicated with 5-HT3 blockerslike ondansetron due to severe hypotension risk.
Bromocriptine:an older ergot derivative, rarely used now given its pulmonary fibrosisrisk (get a baseline chest x-ray and repeat yearly if used).
Dopamine agonists are preferred in younger patientsto delay levodopa-related motor complications, but avoided in patients with cognitive impairment or dementiaand used cautiously in older adults, since psychosis and orthostatic hypotension are more common in that population than with levodopa.
Class adverse effects:nausea/vomiting (30-40%), orthostatic hypotension, dyskinesia, hallucinations/delusions/confusion, impulse control disorders, and sudden sleep attacks(associated with traffic accidents, worth an explicit warning about driving).
Mechanism:Selective inhibition of MAO-B, the enzyme predominating in the striatum that metabolizes dopamine, prolonging dopaminergic activity. All three preferentially hit MAO-B over MAO-A at therapeutic doses. Rasagiline and selegiline are irreversibleinhibitors (propargylamine moiety); safinamide is reversible. Used adjunctively they add up to about 1 extra hour of "on" time.
Rasagiline:the only one FDA-approved as monotherapy in early PD, oral only, 0.5-1 mg once daily, no renal adjustment needed, well tolerated with minimal GI or neuropsychiatric effects.
Selegiline:tablet, capsule, transdermal patch, or ODT (Zelapar); metabolized to L-methamphetamine and L-amphetamine, which explains why it can worsen insomnia and anxiety, especially if dosed late in the day. It can also increase levodopa's peak effect and worsen preexisting dyskinesias or psychiatric symptoms.
Safinamide:add-on to levodopa only (not monotherapy), 50 mg daily, may increase to 100 mg after 2 weeks. Also has a glutamate-release inhibitory action distinct from the other two. Contraindicated in severe hepatic impairment.
Contraindicatedwith or within 14 days of meperidine, methadone, tramadol, cyclobenzaprine, linezolid, and St. John's Wort, serotonin syndrome risk. Use cautionwith SSRIs, SNRIs, and TCAs (not an absolute contraindication, but monitor closely). And separately: the tyramine ("cheese") reaction, aged cheese, cured meats, red wine, and fava beans can trigger a hypertensive crisis if MAO-A is also inhibited, though in practice dietary restriction is mostly a theoretical concern at the selective doses used in PD, current guidance leans toward caution rather than strict avoidance.
Adverse effects:nausea, dyskinesia, impulse control disorders, exacerbation of psychotic symptoms. Avoid selegiline use for CrCl <30.
Mechanism:Block catechol-O-methyltransferase, the enzyme that peripherally converts levodopa to a metabolite that competes for the same amino acid transporter into the brain. Blocking it increases levodopa's AUC by roughly 35%, extends "on" time by 1-2 hours (longer with opicapone), and lets you use a lower levodopa dose for the same effect. These only work as an add-on to levodopa, there's nothing to protect from breakdown without it, so they're never monotherapy.
Entacapone:dosed with every single levodopa dose, up to 8 times a day, max 1600 mg/day. Also available pre-combined with carbidopa/levodopa as Stalevo.
Opicapone:the once-daily option, 50 mg at bedtime, a meaningful convenience advantage over entacapone's dosing burden.
Tolcapone carries a risk of fatal hepatotoxicity. If used, check ALT/AST at baseline and every 2-4 weeks for the first 6 months, then based on clinical judgment. This monitoring burden is why entacapone and opicapone are used far more often in practice. Hepatotoxicity is notreported with entacapone.
Adverse effects:essentially an amplification of levodopa's own side effects (since more levodopa reaches the brain), plus diarrhea and brownish-orange urine discoloration. Avoid nonselective MAO inhibitors concurrently, it disrupts normal catecholamine metabolism.
Amantadine:a repurposed antiviral that's a weak NMDA antagonist and also blocks dopamine reuptake while increasing presynaptic dopamine release. It provides modest benefit for tremor, rigidity, and bradykinesia as monotherapy in mild early disease, but its main modern niche is as the go-to add-on for levodopa-induced dyskinesia(it's specifically anti-dyskinetic, not just anti-parkinsonian). Available as IR and two ER formulations (Gocovri, Osmolex). Renal dose reduction is required: 100 mg/day for CrCl 30-50, 100 mg every other day for CrCl 15-29, and 200 mg every 7 days for CrCl <15 or hemodialysis. Watch for livedo reticularis(mottled skin discoloration, usually lower extremities), common but fully reversible on discontinuation.
Anticholinergics (benztropine, trihexyphenidyl):improve tremor and sometimes dystonic features, but rarely help bradykinesia or gait, so they're a narrow tool aimed specifically at tremor-predominant, younger patients. Avoid in older adultsor anyone with preexisting cognitive impairment, the anticholinergic burden (confusion, sedation, memory problems) lands hardest there. They also slow gastric absorption, which can blunt levodopa's own uptake if given together. Standard anticholinergic adverse effects apply: dry mouth, blurred vision, constipation, urinary retention.
Istradefylline:the adenosine A2A antagonist, adjunct to levodopa for "off" episodes only. 20 mg once daily, 40 mg for patients smoking >20 cigarettes/day (faster CYP1A1/3A4 clearance). Elimination half-life is long, around 80 hours. Avoid strong CYP3A4 inducers; reduce dose with strong CYP3A4 inhibitors. Adverse effects: insomnia, hallucinations, nausea, constipation, take it in the morning with food to help with the insomnia risk.
These aren't rare side effects, they're the expected long-term consequence of levodopa therapy: roughly 10% of patients per yeardevelop them, and they can start as early as 5-6 months in. Risk is higher with younger age at onset and higher cumulative levodopa dose. Recognizing which complication is which, and matching it to the right fix, is one of the highest-yield skills in this chapter.
| Complication | Why it happens | Fix |
|---|---|---|
| End-of-dose "wearing off" | Levodopa's short half-life plus shrinking neuronal dopamine storage capacity; symptoms creep back before the next dose is due | Increase levodopa dosing frequency; switch to CR/ER formulation; add a COMT inhibitor, MAO-B inhibitor, or dopamine agonist; bedtime dosing of a long-acting agent for overnight coverage |
| "Delayed on" / "no on" | Delayed gastric emptying or reduced duodenal absorption keeps levodopa from working on schedule | Take on an empty stomach; use the ODT formulation, or crush/chew IR tablets; avoid CR/SR formulations for this specific problem; consider apomorphine or inhaled levodopa as rescue |
| Peak-dose dyskinesia | Involuntary choreiform (writhing) movements at peak striatal dopamine concentration, from pulsatile receptor stimulation | Smaller, more frequent levodopa doses; reduce adjunct dopamine agonist dose; add amantadine specifically for this |
| "Off-period" dystonia | Sustained, often painful muscle contractions (classically the feet/toes) as levodopa levels wane, most common in early morning | Bedtime dosing of a sustained-release formulation; baclofen; botulinum toxin for refractory cases |
| Freezing / start hesitation | Episodic inability to initiate movement, feet feel "glued to the floor," worsened by anxiety, raises fall risk | Optimize pharmacotherapy; physical therapy; assistive devices; sensory cueing (rhythmic commands, stepping over objects) |
| "On/off" phenomenon | Unpredictable swings between mobile ("on," often with dyskinesia) and akinetic ("off") states, unrelated to dose timing; a sign of becoming refractory to stable levodopa response | Harder to manage than timing-related fluctuations; requires regimen stabilization and sometimes advanced therapy (pump delivery, DBS) |
"Wearing off" is timing-related, "on/off" is not.Wearing off predictably returns symptoms right before the next dose and responds to more frequent dosing. On/off swings happen unpredictably regardless of when the last dose was taken. Mixing these two up on an exam is one of the most common errors.
Peak-dose dyskinesia (too much dopamine effect) is treated by loweringlevodopa dose or adding amantadine. Off-period dystonia and wearing off (too little dopamine effect) are treated by increasingdosing frequency or adding a longer-acting agent. Know which end of the dosing cycle a complication sits on before reaching for a fix, since the two fixes are opposite.
Non-motor symptoms are frequently what actually drives quality of life and caregiver burden, and several have PD-specific drug choices.
| Symptom | Approach |
|---|---|
| Psychosis / hallucinations | Quetiapineis preferred first-line for its low risk of worsening motor symptoms (monitor for metabolic effects). Clozapinealso has low risk of worsening movement but requires monitoring for agranulocytosis and seizures. Pimavanserinis the only drug FDA-approved specifically for PD psychosis, monitor for CYP3A4 interactions and QT prolongation. First step for any of these is usually reducing the causative PD medication (levodopa or an agonist) before adding an antipsychotic. |
| Depression | Treated as its own distinct condition, same as in a non-PD patient: SSRI, SNRI, or TCA. Watch for serotonin syndromeif the patient is also on an MAO-B inhibitor. |
| Dementia / cognitive impairment | Acetylcholinesterase inhibitors (rivastigmine most commonly, also donepezil, galantamine). Reassess whether an anticholinergic PD drug is contributing to the cognitive picture, since that's a reversible confounder. |
| Orthostatic hypotension | Droxidopais FDA-approved specifically for neurogenic orthostatic hypotension in PD, a norepinephrine prodrug. Carries a black box warning for supine hypertension; high-dose carbidopa may blunt its effect. |
| Impulse control disorders | Pathological gambling, hypersexuality, overeating, or excessive spending from dopaminergic overstimulation of the brain's reward circuitry, more common with dopamine agonists than levodopa. Risk factors: younger age, prior history of alcoholism or gambling. Management is slow taperof the causative drug, abrupt cessation risks withdrawal symptoms (irritability, depression, suicidality). |
A potentially fatal withdrawal syndrome from abrupt discontinuation or dose reductionof PD medications, presenting with fever, muscle rigidity, autonomic instability, and altered mental status, onset typically 18 hours to 7 days after the drug change. Risk factors include concurrent antipsychotic use, dehydration, and altered PD-drug pharmacokinetics. This is exactly why drug holidays and any dose reduction must be tapered slowly, never stopped abruptly, and why patients calling about self-directed "drug holidays" need to be redirected to their prescriber immediately.
Avoid metoclopramide and prochlorperazine reflexively. Ondansetron is dopamine-sparing, but remember it's separately contraindicated with apomorphinedue to severe hypotension risk, so check the med list before reaching for it in a patient on apomorphine.
| Parameter | When | Watching for |
|---|---|---|
| Mental status | Every visit, especially after dose changes to agonists, amantadine, anticholinergics, or MAO-B inhibitors | Confusion, hallucinations, delusions, mania |
| Abnormal involuntary movements | Every visit, especially on levodopa or after dose escalation | Dyskinesia, timing relative to dose (peak-dose vs off-period) |
| Blood pressure, standing and sitting | Baseline and each titration of levodopa, dopamine agonists, or droxidopa | Orthostatic hypotension, falls risk |
| Renal function (CrCl) | Baseline and periodically | Dose adjustment triggers for amantadine, pramipexole, ropinirole, apomorphine |
| LFTs (ALT/AST) | Baseline, then every 2-4 weeks for the first 6 months on tolcapone | Hepatotoxicity |
| Bowel movements | Regularly on entacapone, opicapone, istradefylline | Diarrhea (COMT inhibitors) vs constipation (istradefylline) |
| Sleep pattern | Every visit on selegiline, dopamine agonists, istradefylline | Insomnia, daytime sleep attacks (ask specifically about driving) |
| Skin | Each rotigotine patch check; lower extremities on amantadine | Patch site reactions; livedo reticularis |
| Chest x-ray | Baseline and yearly if on bromocriptine | Pulmonary fibrosis |
| "On"/"off" diary | Ongoing, patient/caregiver-recorded | Timing and frequency of motor fluctuations, guides regimen adjustment |