1. Pharmacophysiology

3. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS The amine hypothesis Tricyclics block the amine transporters known as the norepinephrine and serotonin transporters, NET and SERT, respectively. These transporters terminate amine neurotransmission. Blockade of these transporters presumably permits a longer sojourn of neurotransmitter in the intrasynaptic space at the receptor site. MAO inhibitors block a major intraneuronal degradative pathway for the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released.

5. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS Some of the second-generation antidepressants have similar strong effects on amine transporters, whereas others have only moderate or minimal effects on reuptake or metabolism. Countering this simple model of increased synaptic activity is increasing evidence of alterations in presynaptic regulation of neurotransmitter release. Presynaptic autoreceptors respond to increased synaptic transmitter by down-regulating transmitter synthesis and release. Furthermore, some (but not all) of these regulatory receptors may themselves be down-regulated.

6. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS Trazodone, nefazodone, and mirtazapine stand out as agents in which antagonism of subtypes of serotonin receptors (5-HT 2A or 5-HT 2C ) may be important in their action. Mirtazapine is unique in including antagonism of a 2 norepinephrine receptors as presumably contributing to its therapeutic effects. Bupropion has been found to alter the output of norepinephrine in humans following chronic administration through some as yet unidentified primary mechanism as well as occupying about 25% of dopamine uptake transporters (DAT) in the brain as revealed by positron emission tomography. (Since it has been shown that effective doses of SSRIs occupy 80% of serotonin uptake sites, the clinical relevance of 25% DAT occupancy is uncertain.) Thus, even the newest antidepressants can still be categorized as possibly working through serotonergic and noradrenergic effects with the additional possibility of a role for dopamine. Increased synaptic dopamine has often been invoked as relevant to the efficacy of MAOIs.

7. RECEPTOR AND POSTRECEPTOR EFFECTS In tests of postsynaptic effects, especially of the tricyclics, cAMP concentrations have consistently decreased rather than increased. The number of receptors for the neurotransmitters can decrease over the same time course as clinical improvement in patients. The initial increase in neurotransmitter seen with some antidepressants appears to produce, over time, a compensatory decrease in receptor activity, ie, down-regulation of certain postsynaptic as well as presynaptic receptors.

8. RECEPTOR AND POSTRECEPTOR EFFECTS It has long been thought that enhanced serotonergic transmission, albeit mediated through diverse mechanisms, might be a common effect of antidepressants even without an increase in synaptic serotonin. Selective antagonism of either norepinephrine or serotonin receptors as opposed to that of the 5-HT transporter may lead to enhanced extracellular serotonin due to the complex manner in which these neurotransmitters are regulated.

9. RECEPTOR AND POSTRECEPTOR EFFECTS The approach has been to reduce the amino acid precursor of serotonin, tryptophan, in the diet and, by implication, the amount of available neurotransmitter in the brain, since tryptophan availability can be rate-limiting in the formation of serotonin. Severely tryptophan-depleted diets reduce plasma tryptophan and acutely reverse antidepressant responses to SSRIs but not to NET inhibitors.

10. RECEPTOR AND POSTRECEPTOR EFFECTS Similarly, depletion of the norepinephrine amino acid precursor tyrosine can reverse antidepressant effects of the relatively selective NET inhibitor, desipramine. Enhanced serotonin and norepinephrine throughout is necessary for the antidepressant actions of the respective transporter inhibitors. However, tryptophan depletion does not consistently worsen the condition of unmedicated depressed patients. Thus, there is still no clear relationship between serotonin and depression or antidepressant mechanisms in general.

11. ACTIONS OF ANTIDEPRESSANTS ON AMINE NEUROTRANSMITTERS Tricyclics block the amine transporters known as the norepinephrine and serotonin transporters, NET and SERT, respectively. These transporters terminate amine neurotransmission. Blockade of these transporters presumably permits a longer sojourn of neurotransmitter in the intrasynaptic space at the receptor site.

14. ANTI-DEPRESSANTS Tricyclic antidepressants SSRIs Dopamine-norepinephrine reuptake inhibitors Serotonin-norepinephrine reuptake inhibitors Serotonin modulators Norepinephrine-serotonin modulator MAOIs Selective noradrenaline reuptake inhibitor

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16. Tricyclics The first-generation antidepressants demonstrate varying degrees of selectivity for the reuptake pumps for norepinephrine and serotonin but selectivity is much lower than for the SSRIs.

17. Second-generation agents Amoxapine is a metabolite of the antipsychotic drug loxapine and retains some of its antipsychotic action and dopamine receptor antagonism. A combination of antidepressant and antipsychotic actions might make it a suitable drug for depression in psychotic patients. However, the dopamine antagonism may cause akathisia, parkinsonism, amenorrhea-galactorrhea syndrome, and perhaps tardive dyskinesia. Maprotiline (a tetracyclic drug) is most like desipramine in terms of its potent norepinephrine uptake inhibition. Like desipramine, it has fewer sedative and antimuscarinic actions than the older tricyclics. Clinical experience with trazodone has indicated unpredictable efficacy for depression, although it has proved very useful as a hypnotic, sometimes being combined with MAOIs, which disturb sleep.

18. non-SSRI agents Nefazodone, venlafaxine, duloxetine, and mirtazapine are all related to earlier agents in either structure or mechanism of action. Nefazodone is closely related to trazodone but is less sedating. It produces fewer adverse sexual effects than the SSRIs (see below) but is a potent inhibitor of CYP3A4. (Fluvoxamine causes the same inhibition of CYP3A4.) Venlafaxine is a potent inhibitor of serotonin transport and a weaker inhibitor of norepinephrine transport. At lower therapeutic doses, venlafaxine behaves like an SSRI. At high doses (more than 225 mg/d), it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine transporter inhibition. Doses in the range of 225 mg/d or more may confer broader therapeutic effects than SSRIs, but titration up to these doses is needed to control adverse effects.

19. non-SSRI agents Mirtazapine is a potent antihistaminic with greater sedating effects than the other second- and third- generation antidepressants. Its use is also more likely to be associated with weight gain. The hypothesized mechanism of action of mirtazapine combines 5-HT 2 receptor and a-adrenoceptor antagonism and, if established in humans, would be unique among available drugs. Thus, mirtazapine may prove beneficial in patients who can tolerate its sedative effects and do not respond well to SSRIs or cannot tolerate their sexual adverse effects.

20. Selective serotonin reuptake inhibitors These drugs achieve high ratios of SERT versus NET inhibition of 300 to 7000. Fluoxetine was the first SSRI to reach general clinical use. Paroxetine and sertraline differ mainly in having shorter half-lives and different potencies as inhibitors of specific P450 isoenzymes. Racemic citalopram and (S)- citalopram (escitalopram), the most selective SSRIs of all, have achieved very widespread use.

21. MAO inhibitors MAO-A (isoform A) is the amine oxidase primarily responsible for norepinephrine, serotonin, and tyramine metabolism. MAO-B is more selective for dopamine. The irreversible inhibitors available in the USA are nonselective and at the doses used block both forms of the enzyme. Irreversible block of MAO, characteristic of the older MAO inhibitors, allows significant accumulation of tyramine and loss of the first-pass metabolism that protects against tyramine in foods. Because they result in replacement of the normal transmitter (norepinephrine) stored in noradrenergic nerve terminal vesicles with a false transmitter (octopamine), they may cause significant hypotension.

23. 1. What are the specific clinical indications for the use of particular antidepressant medications? 2. What are the relative efficacies of different antidepressant medications? 3. What are the relationships between antidepressant blood levels and response? 4. What are the relative risks of toxicities (e.g., cardiotoxicity) and adverse effects for different antidepressant medications? 5. What should the duration of treatment be before a patient is considered medication- resistant, and does this duration vary among agents? 6. Does the combination of antidepressants from different pharmacologic classes (e.g., SSRIs and tricyclic antidepressants) offer greater efficacy than administration of single agents? 7. What are the comparative efficacies of different antidepressant medications in the continuation and maintenance phases? 8. What are the long-term side effects of chronic use of specific antidepressant medications? 9. What is the required duration of maintenance treatment with antidepressants? 10. What are indications for a trial of discontinuation of maintenance treatment?

24. 1. What are the relative efficacies of different psychotherapeutic approaches in the acute phase of treatment? 2. What components or aspects of specific psychotherapeutic approaches are responsible for efficacy? What common elements of all effective psychotherapeutic approaches are responsible for efficacy? 3. What are the indications (e.g., subtypes of depressive disorders) for use of various forms of psychotherapy? 4. What are the efficacies of particular psychotherapeutic approaches in the continuation and maintenance phases of treatment? 5. Is the use of multiple forms of psychotherapy, either concurrently or sequentially, effective? 6. What are the optimal frequencies of psychotherapeutic contact for the various forms of psychotherapy in the acute, continuation, and maintenance phases?