Pharmacotherapy for Schizophrenia

Question.

My question involves the combining of two psychotropic agents. I am unclear why it is done and why it works. I treat chronically ill patients, mostly with schizophrenia or schizoaffective disorder. They are treated with agents that functionally decrease dopamine, i.e. Haldol, Clozaril etc. If they become depressed, and the depression does not respond to additional neurolpetic, I add an antidepressant. These may increase the dopamine level, as the antidepressants are dopaminergic to varying degrees (i.e. Wellbutrin, Effexor etc.) How do I make sense of this on a biochemical and receptor level?

Answer.

If you are confused about the mechnaism of psychotropic medications – not to mention, medications used in combination – then you are well on your way to understanding! We really do not know how most psychotropic agents “really work” in the first place, though we suspect certain of their pharmacologic actions. Antipsychotics certainly seem to work via blockade of some kinds of dopamine receptors, but – as your question implies – getting the patient better may sometimes require boosting various neurotransmitters, including dopamine!

First of all, consider that the dopamine hypothesis of schizophrenia is itself becoming increasingly more complex, if not outright untenable. We now believe that while some brain regions (perhaps limbic areas) may be exposed to too much dopamine in schizophrenia, other regions (perhaps frontal areas) actually have too little dopaminergic activity. These disparities might explain, respectively, the presence of positive and negative symptoms in schizophrenia. Newer agents, such as the atypical antipsychotics clozapine and risperidone, may block some dopamine receptors (D1, D2, D4), while simultaneously enhancing dopaminergic and/or noradrenergic function in some brain regions. (There is some evidence, for example, that antagonizing the 5HT2 receptor, which these atypical agents do, may lead to increased dopamine “outflow” in some brain regions).

Going back to your question, however, most available antidepressants do not have much of an effect on dopamine – the two you mention, venlafaxine and bupropion – probably do so only at rather high doses (e.g., >350 mg per day of venlafaxine, and >300 mg of bupropion). SSRIs and tricyclics have been found useful in some depressed schizophrenic patients, as have psychostimulants.. While psychostimulants (Ritalin, etc.) would be expected to boost dopamine, SSRIs and tricyclics probably do not (in fact, SSRIs may actually decrease dopamine in some brain regions).

So we might conclude that some depressed schizophrenic patients will improve with increased serotonergic activity, while others might require increased noradrenergic or dopaminergic activity – even in the face of dopamine receptor blockade. This speaks to the probable regional variations in neurotransmitter abnormalities in schizophrenia, and perhaps in schizoaffective disorder (whatever that is!). A good discussion of some of these complex issues may be found in the Journal of Clinical Psychiatry August 1994 Monograph on “serotonin/dopamine antagonists.” Also see Bloom & Kupfer’s excellent volume, Psychopharmacology: The Fourth Generation of Progress (1995), for many articles covering these complex subjects.

It helps me to think of psychotropics as restoring some putative “optimal” balance of neurotransmitters, rather than increasing or decreasing particular ones–rather like tuning the strings on a violin, rather than adding or removing one!