The new antidepressants are generally as efficacious as the older tricyclic antidepressants and monoamine oxidase inhibitors, but have safety advantages. They may be more effective and cost-effective than the older drugs because they are more likely to be taken in an adequate dose for long enough to produce remission and prevent relapse. In addition to depression, the new drugs may have a role in treating anxiety disorders including obsessive compulsive disorder, panic disorder, social anxiety disorder (social phobia), post-traumatic stress disorder and possibly chronic fatigue. They may also help depression in patients with schizophrenia if the depression is not adequately relieved by antipsychotic drugs.


What are the new antidepressants?

The new antidepressants include four different types of drugs (Table 1). They are alternatives to tricyclic antidepressants (TCAs), the non-selective irreversible inhibitors of monoamine oxidases A and B (MAOIs) and tetracyclic antidepressants.

Table 1 The new antidepressants

Selective serotonin reuptake inhibitors

  • citalopram
  • fluoxetine
  • fluvoxamine
  • paroxetine
  • sertraline

Reversible inhibitor of monoamine oxidase A

  • moclobemide

Selective serotonin-noradrenaline reuptake inhibitor

  • venlafaxine

5HT2 receptor antagonist

  • nefazodone


Although some patients may benefit more from drug treatment, psychological treatments are as effective as antidepressants for mild depression. For depression of moderate severity, pharmacotherapy is superior, while for severe depression, electroconvulsive therapy (ECT) is the most efficacious treatment.

About two-thirds of patients will respond to the first drug which is prescribed. One-third of patients will need to change to a second drug and about one-third of those to a third drug. The efficacy of the new antidepressants is similar to that of the older drugs. The new drugs may be more effective as they are more likely to be taken in an effective dose for an adequate time and are less likely to be toxic. This is an advantage because there is now recognition of the importance of patients being well for an extended period of time (6-12 months) before antidepressant treatment is reduced and ceased. The longer a patient is well, the more likely they are to remain well.

New antidepressants may be used in adolescents and are safer than TCAs in this group. There are few data on the efficacy and safety of these drugs in children. The greater tolerability of newer drugs makes them antidepressants of choice in the elderly. Absent or lesser anticholinergic effects are especially helpful in those with cognitive decline.


Which antidepressant should I choose first?

The doctor's familiarity with a particular antidepressant and confidence in its use can be a potent factor in the choice of drug. Doctors need to be familiar with several drugs to provide a reasonable range of choices for a given patient. Data regarding the superiority of one antidepressant over another are limited. On average, most antidepressants are similar in efficacy. There are no major cost-effectiveness differences between the newer drugs. The cost-effectiveness of the newer drugs is similar to or better than that of TCAs for treating an episode of depression even though the per tablet cost may be higher.

Patient's history

There is no ideal antidepressant. The patient's past medication history may suggest the initial antidepressant to choose especially if they previously responded to one of the newer drugs. Do not inappropriately reject a drug. A history of being unable to tolerate a drug may reflect a discontinuation syndrome from earlier treatment, drug interaction, or too rapid an escalation of dose. Similarly, a failure to respond may have resulted from too low a dose or too short a therapeutic trial. A previous response to a serotonergic TCA (e.g. clomipramine) may suggest that the drug to use is a selective serotonin reuptake inhibitor (SSRI) or nefazodone. A higher dose of venlafaxine may be appropriate if the patient has previously responded to a noradrenergic TCA (e.g. nortriptyline). Yet any of these new antidepressants may help all types of depression.

Co-morbid conditions may guide the selection. For example, an SSRI may be the treatment of choice for depression in patients who have obsessive compulsive disorder or panic disorder. Moclobemide or an SSRI may be appropriate if there is a co-morbid social anxiety disorder.


Drugs with a short half-life are useful as it will take less time, for the one-third of patients who will not respond, to change to another antidepressant. While drugs with a longer half-life can result in extended changeover periods (e.g. following higher doses of fluoxetine), they are useful for patients who may miss an occasional dose or are especially concerned about the possibility of discontinuation effects.

Modified-release capsules (e.g. venlafaxine modified-release) may extend the release of a short half-life drug allowing once a day dosing rather than twice a day. In changing from standard to modified-release, the total daily dose should be unchanged.

Most antidepressants are metabolised by the liver. Some have active metabolites although only that of fluoxetine (norfluoxetine) contributes substantially to its action and elimination half-life. Drugs which inhibit hepatic cytochrome P450 isoenzymes increase the potential for interactions. The pattern of enzyme inhibition differs between SSRIs as some inhibit one enzyme, while others may inhibit more than one. Enzyme inhibition reverses as soon as the inhibiting drug is washed out, without delays for enzyme synthesis. Interactions can result in toxic or even fatal concentrations of drugs even when co-prescribed at normal therapeutic doses. For example, prescribing an SSRI with either an MAOI or a TCA risks the serotonin syndrome. As SSRIs can interact with many drugs their potential for adverse interactions should be checked before co-prescribing. Unfortunately, the product information may not state which interactions are clinically important.

Adverse reactions

Adverse effects may suggest which antidepressant to use. Moclobemide or nefazodone may be suitable for patients concerned about sexual adverse effects with other drugs. Concerns about increases in blood pressure at higher doses may limit the use of venlafaxine. All drugs may cause unacceptable (or desirable) sedation for some patients, although this is more likely with nefazodone.

Doctors are usually aware of acute adverse events. They may not be so aware of adverse events which emerge with continued use e.g. sexual adverse events like anorgasmia. These events may reduce patient compliance with long-term therapy and will remain undetected unless the patient is specifically asked about them.

Discontinuation syndromes can occur with all antidepressants when they are stopped. These are less when the drug has been used for a short time, or in a low dose. They are less likely to occur with a slow tapering discontinuation, although this may substantially delay the transition to an alternative drug if there has been no response or the drug has not been tolerated. Discontinuation syndromes are infrequently reported with the long half-life SSRI, fluoxetine. Surprisingly, they are also rare with the short half-life moclobemide. They appear to be more common with other shorter half-life antidepressants. This includes venlafaxine, nefazodone and the SSRI, paroxetine (seemingly more than other SSRIs). Missed doses and `drug holidays' compromise antidepressant efficacy and may be associated with withdrawal effects.


Combining antidepressant treatments

Although there are advocates for combining antidepressants with different receptor profiles for presumed added efficacy, there is scant scientific evidence for the effectiveness of such combinations over treatment with a single efficacious drug. In contrast, there is an abundance of data on toxic and fatal interactions, especially those that lead to cardiac arrhythmias, or the serotonin syndrome. In due course, there may be support for the use of some combinations in particular circumstances, but the balance of evidence at this time suggests that there may be increased risk to the patient with doubtful increased benefit. Augmentation of antidepressant response with drugs like lithium may be an option in patients whose response is otherwise inadequate.

There are no data to support greater effectiveness of ECT in combination with antidepressants. The degree and speed of recovery is unaffected whether or not an antidepressant is added to ECT. In contrast, some data suggest greater toxicity with the combination. Antidepressants are usually used at the end of a course of ECT, but not normally during the course of ECT.


Indications other than depression

The efficacy of the newer antidepressants is not restricted to depression. They can help in other disorders including obsessive compulsive disorder, panic disorder, some phobias, post-traumatic stress disorder and residual depression after schizophrenia is treated with antipsychotics. These indications are mostly not approved by the Therapeutic Goods Administration or the Pharmaceutical Benefits Scheme in Australia. Such drug use must be combined with psychological and social therapeutic interventions.

Obsessive compulsive disorder

The antidepressants that affect serotonin are uniquely efficacious in the treatment of obsessive compulsive disorder (OCD). These include the SSRIs, with some support for the efficacy of venlafaxine and nefazodone, but not moclobemide, despite its 5HT activity. Although these drugs are significantly better than placebo, they do not cure OCD. In practice, they may only reduce symptoms by 20-25%. These modest gains can have major benefits clinically, because patients can use cognitive behaviour therapy (CBT) more successfully when the severity of their OCD has been reduced. For those with co-morbid depression, the relief of the depression can also enable the patient to benefit from CBT. Patients with OCD tend to relapse when they discontinue their medicines. Those who also received CBT may relapse less.

Approved drugs are clomipramine (a TCA), fluoxetine, fluvoxamine, paroxetine and sertraline. Paroxetine is also approved for relapse prevention.

Panic disorder

Panic disorder, or episodic bouts of severe anxiety of relatively short duration, is a disabling disorder, frequently associated with agoraphobia. Approximately half the patients with panic disorder will experience depression. All the new antidepressants appear effective for both panic and associated avoidance behaviour. The onset of action is 2-6 weeks and occurs even in the absence of depression. With some drugs and patients, the dose to control panic may be higher than the usual dose for depression. If very rapid control of panic symptoms is required, benzodiazepines are uniquely effective, although such use is rarely indicated.

Approved drugs are paroxetine (including for relapse prevention) and the benzodiazepine alprazolam (which is not an antidepressant).

Social anxiety disorder (social phobia)

Social anxiety disorder (social phobia) is unique among anxiety disorders with its early onset, often in early childhood. It is particularly disruptive to normal development and there are common co-morbidities. Approximately 75% of patients have co-morbid disorders including agoraphobia, specific phobias, depression and substance abuse. New antidepressants may help the concurrent treatment of co-morbid disorders, but none are currently approved for this indication. Moclobemide has been the most extensively studied antidepressant for treating social phobia. SSRIs are effective and it is likely that all the new antidepressants work. Paroxetine has been approved for this disorder. Improvement can continue for up to two years, and may not plateau by 6-8 weeks, as is commonly the case in treating depression. The concurrent use of CBT may be a useful adjunct and may limit the relapse, which can occur when medicines are withdrawn.

Post-traumatic stress disorder

There is controversy as to the most appropriate treatments for post-traumatic stress disorder (PTSD). The new antidepressants may be helpful for co-morbid depression and anxiety disorders and have a lower risk of interaction with alcohol (although concurrent alcohol use is discouraged). Currently, none are approved for this indication.

Chronic fatigue

There are limited data to suggest that moclobemide may be helpful for some patients with chronic fatigue. Other antidepressants may help, but data are currently lacking. Some depressed patients present with somatic symptoms, such as loss of interest and loss of energy, rather than with depressed mood and may be misidentified as having chronic fatigue. They would be expected to respond to antidepressants in the same way as other depressed patients.

Schizophrenia and depression

There is no primary role for antidepressants in schizophrenia. Current data suggest that patients with schizophrenia who are treated with an antipsychotic, but have continued depressive symptoms, may improve with the addition of an antidepressant. Antidepressants which inhibit the metabolism of antipsychotics may increase the risk of adverse events such as increased extra pyramidal symptoms. The potential for a specific antidepressant/antipsychotic interaction should be reviewed before prescribing. The TCAs were thought to worsen psychosis, but this is now questioned.



The newer antidepressants herald an era of better-tolerated drugs that are safer, and less toxic in overdose. They are more likely to be taken in an effective dose for a sufficient period of time to achieve remission and to prevent relapse. There are appreciable clinical and economic advantages over traditional antidepressants. They are perhaps better regarded as broad spectrum psychotropic drugs for the neurotic disorders and the depressive phase of manic depressive psychosis (bipolar disorder). They also have a role in the treatment of persisting depression associated with schizophrenia for those already treated with antipsychotics.

The newer antidepressants, even within classes, are appreciably different from one another. One drug in a class may be tolerated and responded to by a particular patient, while another may not. One drug cannot automatically be substituted for another. Rather, they provide a diversity of medicines that increase the likelihood a patient will receive effective treatment. The discovery of new indications for these drugs, and the insights these provide as to the nature of psychiatric disorders, add to our awareness of our limited knowledge, rather than a comfortable reassurance that we know it all.

Associate Professor Tiller has been a consultant to, or conducted research sponsored in whole or in part by, producers of all the new antidepressants, as well as producers of tricyclic antidepressants, monoamine oxidase inhibitors, antipsychotics and benzodiazepines.

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Self-test questions

The following statements are either true or false.

1. Venlafaxine may cause a rise in blood pressure at high doses.

2. Moclobemide is not effective in the treatment of obsessive compulsive disorder.

Answers to self-test questions

1. True

2. True

John W.G. Tiller

Associate Professor and Reader, University of Melbourne, The Royal Melbourne Hospital

Director, Academic Psychiatry Unit, Albert Road Clinic, Melbourne