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The Burden of Acute and Long-Term Side Effects

Adverse Effects

In tandem with the benefits of antipsychotic medications are significant risks associated with their use. These risks are primarily acute and chronic neurological adverse effects, such as parkinsonism, akathisia, dystonia, and tardive dyskinesia, that can range in intensity from mild to severe. Newer atypical antipsychotic agents do not cause agranulocytosis, and usually cause fewer parkinsonian symptoms than the typical agents when given in doses at the lower end of their therapeutic range. Side effects include (1) acute dystonic reaction (2% of patients, onset within hours); (2) drug-induced Parkinsonism (20-40% of patients, onset 5-30 days); (3) akathisia (20% of patients, onset 5-60 days); (4) tardive dyskinesia (20% of patients, onset 3 months to years); (5) neuroleptic malignant syndrome (0.5-1% of patients, mortality around 20%); (6) metabolic impairments among which weight gain (15% of patients within the first weeks of treatment — 50% of patients in the long term) and diabetis mellitus (6% of patients) are prominent.

Highly Compromised Compliance

Acute side effects of antipsychotics, generally referred to as extrapyramidal side effects, are often quite uncomfortable for patients and may compromise compliance with an otherwise beneficial antipsychotic medication regimen. Extrapyramidal effects by themselves have been related to a poor outcome, a compromised compliance, secondary negative symptoms, cognitive parkinsonism, and depression.


Antipsychotic-induced extrapyramidal effects, along with the conditions under which they occur in the individual patient, are insufficiently understood, and display considerable ethnic variation. Given current knowledge, it is not possible to make any predictions of whether a particular patient will develop side effects — and to what extent — under a particular antipsychotic treatment. Clearly, the assessment of ethnicity-specific predictors by means of objective laboratory methods would greatly improve antipsychotic drug therapies and ultimately lead to a more personalized and better tolerable medicine.


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premature withdrawal
Fig. 4: Cumulative rates of premature withdrawals under amitriptyline (TCA; yellow triangles) and oxaprotiline (investigational noradrenaline uptake inhibitor; green circles) versus placebo (red squares). Premature withdrawals occur early under placebo (lack of effect), while drop-outs under amitriptyline typically occur after one week of treatment when dosages reach therapeutical levels. This in contrast to the reduced, unspecific side effect profile of oxaprotiline, where premature withdrawals occur at a constant rate over the entire observation period.
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