Cautions
The therapeutic use of these drugs in hypertension, psychosis, and chorea needs to be very carefully monitored for psychiatric complications. Although occasionally useful for these indications, VMAT2 inhibitors are accompanied by adverse effects that might precipitate psychiatric evaluations, particularly depressed mood, suicidal thoughts, and suicidal behaviors. In one case series, 18% of the patients treated with reserpine for hypertension were found to have depressive symptoms after an average exposure of 4.5 months.30 Unfortunately, in the largest clinical trial of tetrabenazine in patients with Huntington disease, 1 of the 22 study participants committed suicide.29 An interesting and unanswered question is how so many participants actually avoid depressive symptoms.

VMAT2 inhibitors have been used clinically as diagnostic tools. Several ligands appear useful as positron emission tomography agents in clinical medicine. Neuronal loss has been documented in Parkinson disease and after methamphetamine abuse, and increased monoaminergic innervation has been detected in Tourette syndrome using the radioligand dihydrotetrabenazine (DTBZ), a related metabolite of tetrabenazine.31-33 Bohnen and colleagues34 found a 0.5% age-related decline in striatal DTBZ binding in normal participants and significant correlation between DTBZ-binding asymmetry and clinical asymmetry in patients in the early stages of Parkinson disease. Caution is necessary, however, because interpretation of alterations in VMAT2 binding can be problematic, since total VMAT2 binding could reflect either the total number of neurons or the number of VMAT molecules per neuron. The regulation of total vesicle number and VMAT2 expression per vesicle remain unresolved and controversial topics.35,36

DTBZ binding and VMAT2 immunoreactivity were found to be decreased in postmortem brain tissue from a large series of cocaine users compared with matched nonusers.37,38 Follow-up studies based on dopamine cell counting indicate that the decrease was caused by neuronal loss rather than a decrease in the VMAT content of individual neurons, which was not altered in in situ hybridization experiments.39,40 VMAT2 diminution was related to increased signs of depressive disorders, a complication of long-term cocaine use. In addition to decreased VMAT2 measures and cell loss, the same cocaine users displayed increased binding to the DAT,41 most likely related to an increase of DAT on the neuronal surface.17 Such a simultaneous up- regulation is postulated to decrease transsynaptic signaling and mitigate the effects of excessive synaptic dopamine (Table 3).

These dopaminergic adaptations may contribute to depression and withdrawal symptoms after cessation of cocaine use, perhaps more than to long-term craving. Withdrawal and sustained depression versus long-term craving, although related, may best be thought of as distinct aspects of cocaine dependence that may require unique therapies.42

Experimental therapies
Both reserpine and tetrabenazine have been researched as treatments for cocaine and methamphetamine dependence, because each drug should theoretically diminish dopamine-based signaling and its role in eventual reward.43,44 Such an effect appears to parallel recent findings that disulfiram, a dopamine synthesis inhibitor, is helpful for cocaine dependence.45 Thus, antidopaminergic approaches might be tailored for those patients who are particularly troubled by the intensity of an acute cocaine "rush." Unfortunately, these treatments might also increase the risk of withdrawal symptoms and depression. Interestingly, alterations in VMAT2 function have been found to affect ethanol intake in animals.46

Recently, Riddle and colleagues36 have demonstrated that methamphetamine and cocaine can alter VMAT2 trafficking and function through mechanisms that might contribute to symptoms and potentially could be reversed for therapeutic effect. In addition, animal studies with a newly designed VMAT2 inhibitor, lobeline and related analogs, which may have additional effects other than VMAT2 inhibition, suggest that this group of drugs decreases behavioral response to methamphetamine, while also decreasing self-administration.47 Furthermore, a new class of ligands for the VMAT2, structurally unique 3-amino-2-phenylpropene derivatives, is being developed with potential effects that have yet to be explored.48

Drugs that could enhance VMAT2 function might be neuroprotective. Heterozygous knockout mice show hypersensitivity to the neurotoxic effects of VMAT2 substrates, such as MPP+, and they display more than double the dopamine cell loss compared with their wild-type littermates.49 Other studies indicate that blockage or loss of VMAT2 function may contribute to accelerated neuronal loss.50,51 However, drug therapies that target VMAT2 function must alter the function of an intracellular target, which is perhaps more elusive and difficult to uniquely manipulate than a target molecule that protrudes through the cell wall. Although complex, the therapeutic possibilities are exciting.

Biographical vignette
The Nobel laureate Ernest Hemingway, whose writings widely influenced 20th century ideas about adventure and heroism, received reserpine treatment for several years in the late 1950s. During this time, he was frequently discouraged and slowly lost weight and physical strength. He found it difficult to concentrate on his writing or achieve an acceptable artistry.

Hemingway was often irritable and bickered frequently with his wife. He was disheartened by his inability to resolve pressing financial obligations and a legal dispute with the IRS.

Hemingway was obsessed with suicide, and clearly envisioned it as the ultimate act of self-control. When Ernest was 29, his father Clarence--a physician--committed suicide using his own Civil War revolver.

On November 30, 1959, Hemingway was admitted for psychiatric care. By this time, the deleterious effects of reserpine had been recognized, and the drug was discontinued. A course of electroconvulsive therapy (ECT) was begun that lasted through January 1960. Hemingway improved and returned home to Ketchum, Idaho. He immediately immersed himself in several difficult writing projects, including finishing the novel, The Garden of Eden, for which he had amassed over 2000 manuscript pages. This novel was a project the 61-year-old Hemingway, recovering from ECT and years of heavy drinking and severe depression, was unable to adequately complete.

During this period, he provided advice to Fidel Castro about managing the US media, but Hemingway was discouraged when Castro evoked Hemingway's name as supporting executions he ordered. In addition, it became clear that Hemingway would not be able to return to his beloved home in Cuba nor was he able to make progress with his financial problems or IRS dispute. He was rehospitalized in April and received further ECT sessions. He appeared suddenly brighter in June and was discharged home. After an apparently happy homecoming, he shot himself the next morning.52

Clearly, a number of biological, psychological, and situational factors contributed to Hemingway's depression and suicide. His relapse and ultimate suicide occurred many months after the physiological effects of reserpine had abated. However, the protracted course of his depression and its damaging effects on his marriage, financial situation, and confidence in his ability to work might have been repairable at an earlier stage if reserpine had been discontinued sooner.
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