A brave new era of IV psychopharmacotherapy

Most psychiatrists generally avoid start­ing an IV line on their patients these days, but delivering psychotropic medi­cations by infusion has been employed in psychiatry for decades—mainly in cases of acute psychiatric emergencies.

IV pharmacotherapy might be evolv­ing, however, to address the treatment of severe, chronic, intractable, and dis­abling disorders that have failed to re­spond to multiple oral formulations. In addition, IV therapy might be ex­ploited to hasten onset of a therapeutic response.

In short, IV delivery of psychotropics might soon become a routine psychiat­ric “procedure.”

In the past

Apart from the desperate measures of pentylenetetrazol-induced seizures for depression and insulin coma for schizophrenia—both eventually dis­carded—psychiatrists have used IV pharmacotherapeutic interventions since the dawn of psychopharmacology in the 1950s. These include:

The present

Recently, a mini-avalanche of novel studies has signaled a paradigm shift to IV therapy for refractory unipolar and bipolar depression.

Ketamine. Administering the N-methyl-d-aspartate (NMDA) glutamate recep­tor antagonist ketamine (a cousin of phencyclidine and a well-known drug of abuse with psychotogenic properties) by IV infusion (0.5 mg/kg) produces rapid improvement, sometimes com­plete remission, of chronic, treatment-resistant depression. The effect seen in 1 or 2 hours matches what oral antide­pressants accomplish in 6 to 8 weeks in a responsive patient.^1,2 The response to IV ketamine lasts approximately 1 week and is initially associated with transient dissociation.

Another reported benefit of IV ket­amine is rapid reversal of suicidal intent.³ This effect is envisioned as a fu­ture alternative to hospitalizing patients brought to the emergency room after a suicide attempt.

To be clear: The long-term (main­tenance) safety and efficacy of re­peated infusions of IV ketamine to maintain response in chronic, treat­ment-resistant depression has not been studied.

IV ketamine therapy for severe de­pression is a dual paradigm shift: 1) it uses the IV route and 2) it modulates the glutamate ion-channel receptor NMDA—a major departure from the 50-year-old monoamine hypothesis of depression, in which a deficit of se­rotonin and/or norepinephrine was proposed. The mechanism of action of IV ketamine appears to be instant trig­gering of neuroplasticity in the mam­malian target of rapamycin (mTOR), as observed in animal studies. A sig­nificant surge in brain-derived neuro­trophic factor appears to be involved as well.

Scopolamine. Another novel IV treat­ment for depression was reported re­cently,⁴ based on old studies in which tearfulness and dysphoria were induced by increasing cholinergic activity with IV physostigmine. The anticholinergic drug scopolamine was administered to depressed patients by pulsed IV infu­sion (4.0 μg/kg over 15 minutes), and rapid improvement in depression was observed within 72 hours in patients with unipolar and bipolar depression. Anticholinergic side effects were mild; women responded better than men.

Nitroprusside. A similar breakthrough with IV pharmacotherapy was recently reported in schizophrenia, in which tra­ditional oral antipsychotic treatment is limited to suppressing positive symp­toms, leaving negative symptoms and cognitive deficits unchanged. The old antihypertensive drug nitroprusside, which modulates nitrous oxide and, by extension, NMDA, was adminis­tered IV to a small sample of patients with schizophrenia.⁵ Significant im­provement was observed not only in positive (psychotic) symptoms, but also in negative and cognitive symp­toms. Improvement occurred within a few hours and lasted for as long as 4 weeks. Studies are underway to repli­cate the investigators’ findings about this potentially ground-breaking and novel approach to schizophrenia.

For the future

Given these recent successes, it is rea­sonable to speculate that IV drugs might someday become a major tool in the practice of psychiatry—tran­scending emergent uses (suicidal, homicidal, and delirious states) and becoming a mainstream treatment for acute episodes of psychosis, mania, depression, and anxiety. In addition, research might reveal that medica­tions already approved for oral deliv­ery exert a more robust response and a more rapid onset of action when delivered IV—assuming no serious safety issues arise.

Advances in our understanding of the neurobiologic basis and patho­physiology of psychiatric disorders might provide clues to agents that are not even on the current radar screen of psychiatry’s pharmacopoeia. Treatment-resistant conditions are ob­vious initial candidates for IV phar­macotherapy, but so might be acute episodes of psychosis, mania, and de­pression, and panic attacks. Just as sta­tus epilepticus requires IV, rather than oral, delivery of an anticonvulsant, we might conceptualize acute psychotic, mood, and anxiety episodes as emer­gent conditions of status psychiatricus that require rapid stabilization with IV medication instead of a pill.