When one antidepressant is partially but not completely effective, increasing number of doctors around the world for very many years have been giving patients a second antidepressant in addition to the first.   This protects the patient from losing the benefits of the first antidepressant, and allows a trial of the benefits of the second antidepressant to be added.   The risks of such a procedure are very low.   Almost 80% of Australian psychiatrists have stated in a confidential survey that they have used this technique, and two-thirds of a group of 300 GPs in a recent survey have continued or initiated this technique.




UK: FROM NICE GUIDELINES OCTOBER 2009 (A British Government expert body)

Augmenting an antidepressant with another antidepressant

Combining antidepressant drugs with different modes of action is increasingly used in clinical practice. Combinations of serotonergic and noradrenergic drugs may result in a ‘dual action’ combination while combinations of serotonergic drugs with different modes of action may be expected to increase serotonergic neurotransmission more than either drug alone. While the efficacy of these combinations may be additive (this is not proven for the majority of combinations), so too may the toxicity.(pg 404)


CANADA: An article in a magazine written for GPs in 2002(!) states “The use of combination antidepressants is common in clinical practice”

from Treatment of depression in primary care, by To et al,

British Columbia Medical Journal 2002; 40: 479-484


USA: “90% of private practice psychiatry is combination antidepressants”

Treatment of Depression in Primary Care.

UUSA: To A, Oeter H, Lan RW

British Columbia Medical Journal 2002; 44:479-484



40% of patients get good long-term benefits from any single antidepressant, 15% get only short-term benefit and 15% get only partial benefit.   Thirty percent do not respond at all to the first antidepressant they are given, but may respond to a different antidepressant.    If there is no response at all, there is no point continuing an antidepressant after 3-4 weeks, and no point in increasing the dose.  Stopping that antidepressant and starting a new one is the next logical step.   There is no way of predicting who will respond to which antidepressant, so the choice is based on the doctor’s knowledge of various different antidepressants, and the side-effects of different antidepressants.





In standard psychiatric practice, as it has been taught in Australia for many years, the advice to doctors is to stop the first antidepressant gradually, wait some time for the antidepressant to get out of the patient’s bloodstream, and then start a new antidepressant, to avoid the situation where two antidepressants are in the patient’s bloodstream simultaneously.   However, most patients who have this practice imposed on them, get worse, and many patients become more distressed and more suicidal while this process takes place.   Furthermore, there is the definite risk, as described above, that the next antidepressant will not work at all!   The whole procedure then has to be repeated.   The process of stopping medication, waiting for the medication to be totally eliminated from the bloodstream and waiting for the new antidepressant to be give a fair trial will take 6-8 weeks in general.   This is a long time for patients who are suffering, especially if their suffering worsens with the withdrawal of a partially effective antidepressant.   As one patient stated, “Washouts are hell”.

Note: ADRAC in October 2009 have advised that this is the safest technique.





Since the introduction of Prozac in 1990 approximately, psychiatrists and GPs all over the world have progressively been trying the effects of giving a second antidepressant as an extra medication when the first antidepressant has partially but obviously helped.   There have been many experiments and trials of this technique, published in prestigious medical specialist journals around the world.    There are many individual patients who have benefitted, and of course many patients for whom the therapy has not worked particularly well.   However, when given a choice, many patients insist on their right to try this extra step, provided it is reasonably safe, but understanding that nothing in medicine is guaranteed 100% safe, as there is so much we do not know about the human brain and body.





In the United States and in Canada, combining two antidepressants in the treatment of depression is very common.   It is so common that articles are written in GP medical magazines in these countries giving family doctors advice on what combinations to use and how to use them.   In Britain, combination antidepressants are a recognised part of the protocol, as one step in treating resistant depression.


In Australia, there has been a strong objection to this technique by a number of influential psychiatrists, who made it very clear they were strongly opposed to allowing any doctor to do this.   However, the author of this site, Dr. David Horgan, some years ago sent out a questionnaire to all doctors involved in psychiatry in Australia, asking for a questionnaire to be returned anonymously.   It transpired that almost 80% of these doctors and psychiatrists had used this technique at some stage, usually in secret because of the pressures they felt.   This survey and its results were published in Australasian psychiatry, one of the specialist publications of the Royal Australian & New Zealand College of Psychiatrists.   In 2008, a research company contacted 300 Australian GPs to conduct a telephone survey, and one of the questions asked was how often they gave patients combined antidepressants.   66% of the GPs stated they had done this, and most GPs stated they intended to do it more often in the future.





There is a rare condition caused by antidepressant medications called the Serotonin Syndrome, which in the majority of cases is a mild condition that resolves spontaneously, but in extreme cases has caused death.   Unfortunately, this is similar to very many medications used in medicine, such as rare cases of death when people take penicillin.


In contrast, certain antidepressant combinations are considered so safe that really no precautions are required.   For example, a large trial of treatments in resistant depression (the STAR*D Project) used certain combinations of antidepressants as a routine option in the trial, with no safety precautions required, and no formal warnings felt necessary.   This was a trial of about 4,000 patients, formally approved by the US Government Department of Health.


In fact, figures from ADRAC (the Australian body monitoring adverse drug reactions) show rare reports of the Serotonin Syndrome, with most of them being due to either single antidepressants or an interaction between the painkiller Tramadol and SSRI antidepressants.   Even St. John’s Wort on its own has been reported to cause some degree of the Serotonin Syndrome!   It does seem the serious Serotonin Syndrome reactions involve a rarely used group of antidepressants known as MAO Inhibitors (typical examples being Parnate, Nardil and Aurorix) when combined with other antidepressants, so this combination should be avoided except by experts in the area of combination antidepressants.





In some cases, definitely yes, and in some cases apparently not.   Formal academic clinical trials to prove the effectiveness of combination antidepressants are very complex and very expensive to run, and therefore are rarely used.   There is no overwhelming body of evidence in favour of combination antidepressants, otherwise this technique would be routinely used by doctors all over the world.   On the other hand, for patients who have tried a number of different antidepressants, many such patients feel they have nothing to lose (apart from the statistically rare risk of Serotonin Syndrome of mild to intense severity), they feel they are losing out drastically in terms of their life and relationships, and they feel they have possibly everything to gain.





Traditional techniques in psychiatry include the addition of lithium and of thyroid hormone to make antidepressants work better.   In reality, significant benefits are rarely achieved with these approaches.   However, for very many patients, there is a marked benefit in the addition of low dose atypical antipsychotics / mood stabilisers (Zyprexa, Seroquel, Abilify, Solian, Risperdal, Invega) to partially effective antidepressants.   The advantage of this approach is that there is no particular risk of Serotonin Syndrome.  The disadvantage is that these drugs are normally quite expensive, and not subsidised under Australian PBS regulations, unless your prescribing doctor feels you meet specified criteria which allow these medications to be prescribed under the PBS.




Important Disclaimer:  This site is medical information only, and is not to be taken as diagnosis, advice or treatment, which can only be decided by your own doctor.



One thought on “Combining 2 Antidepressants

  1. A.a says:

    what are side effects of adding Prozac 20mg to current combination of Zyprexa 20mg plus Invega 6mg for resistant phsychosis

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