TERMINOLOGY AND PRINCIPLES OF COMBINING
ANTIPSYCHOTICS WITH A SECOND MEDICATION: The term "combination" includes virtually all the ways in which one medication may be added to another. The other commonly used terms are "augmentation" which implies an additive effect from adding a second medicine to that obtained from prescribing a first, an "add on" which implies adding on to existing, possibly effective treatment which, for one reason or another, cannot or should not be stopped. The issues that arise in all potential indications are: a) how long it is reasonable to wait to prove insufficiency of response to monotherapy; b) by what criteria that response should be defined; c) how optimal is the dose of the first monotherapy and, therefore, how confident can one be that its lack of effect is due to a truly inadequate response? Before one considers combination treatment, one or more of the following criteria should be met; a) monotherapy has been only partially effective on core symptoms; b) monotherapy has been effective on some concurrent symptoms but not others, for which a further medicine is believed to be required; c) a particular combination might be indicated de novo in some indications; d) The combination could improve tolerability because two compounds may be employed below their individual dose thresholds for side effects. Regulators have been concerned primarily with a and, in principle at least, c above. In clinical practice, the use of combination treatment reflects the often unsatisfactory outcome of treatment with single agents.
ANTIPSYCHOTICS IN
MANIA: There is good evidence that most
antipsychotics tested show efficacy in acute
mania when added to
lithium or
valproate for patients showing no or a partial response to
lithium or
valproate alone. Conventional 2-armed trial designs could benefit from a third
antipsychotic monotherapy arm. In the long term treatment of
bipolar disorder, in patients responding acutely to the addition of
quetiapine to
lithium or
valproate, this combination reduces the subsequent risk of relapse to depression,
mania or mixed states compared to monotherapy with
lithium or
valproate. Comparable data is not available for combination with other
antipsychotics.
ANTIPSYCHOTICS IN MAJOR DEPRESSION: Some atypical
antipsychotics have been shown to induce remission when added to an
antidepressant (usually a SSRI or
SNRI) in unipolar patients in a major depressive episode unresponsive to the
antidepressant monotherapy. Refractoriness is defined as at least 6 weeks without meeting an adequate pre-defined treatment response. Long term data is not yet available to support continuing efficacy.
SCHIZOPHRENIA: There is only limited evidence to support the combination of two or more
antipsychotics in
schizophrenia. Any monotherapy should be given at the maximal tolerated dose and at least two
antipsychotics of different action/tolerability and
clozapine should be given as a monotherapy before a combination is considered. The addition of a high potency D2/3 antagonist to a low potency antagonist like
clozapine or
quetiapine is the logical combination to treat positive symptoms, although further evidence from well conducted clinical trials is needed. Other mechanisms of action than D2/3 blockade, and hence other combinations might be more relevant for negative, cognitive or affective symptoms.
OBSESSIVE-COMPULSIVE DISORDER: SSRI monotherapy has moderate overall average benefit in OCD and can take as long as 3 months for benefit to be decided.
Antipsychotic addition may be considered in OCD with
tic disorder and in refractory OCD. For OCD with poor insight (OCD with "psychotic features"), treatment of choice should be medium to high dose of SSRI, and only in refractory cases, augmentation with
antipsychotics might be considered. Augmentation with
haloperidol and
risperidone was found to be effective (symptom reduction of more than 35%) for patients with
tics. For refractory OCD, there is data suggesting a specific role for
haloperidol and
risperidone as well, and some data with regard to potential therapeutic benefit with
olanzapine and
quetiapine.
ANTIPSYCHOTICS AND ADVERSE EFFECTS IN SEVERE
MENTAL ILLNESS: Cardio-metabolic risk in patients with severe
mental illness and especially when treated with
antipsychotic agents are now much better recognized and efforts to ensure improved physical health screening and prevention are becoming established.