Effectiveness of Antidepressants
Erin Hagness, Georgina Morton, Stephen Oates, Xun Li

The New York Times: Before you Quit Antidepressants
Media Item

Underlying journal article:

Synopsis: A meta-analysis was published in 2009 seemingly showing that antidepressents are no better then placebos for mild to moderate depression. Dr Richard Friedman writing in the NYT argues that it still makes sense to take antidepressants, is he right?

Marker's comments here...

1. Introduction

This article was published in the Mind column of the Health Section in the New York Times (11/01/2010). It is written by regular contributor Dr. Richard A. Friedman who is a Professor of clinical Psychiatry at Weill Cornell Medical College. (Dr Friedman is actively involved in clinical research for drug treatments of mood disorders). The article is in response to a published metanalysis (Fouriner et al. 2009) which examined the effectivness of two types of antidepressants - Impramine and Paxil. In particular the paper was interested in controlling for the placebo effect and assessing how antidepressant effectivness was related to the severity of the depression as measured by the Hamilton Depression Rating Score (HDRS).

This paper found that:
“True drug effects (an advantage of ADM [antidepressant medication] over placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms.” (p. 51)
HDRS_Change_vs_HDRS_Score.jpgFig 1. Table from Fouriner et al. (2009) p. 51

Dr Friedman’s response can be seen as an attempt to argue that it is still worthwhile for consumers to take antidepressants even if they have only mild or moderate depression. This is centred around the following points:1.-The new study stands in contrast to much earlier evidence2.-It only covers a small subset of available medication, typically the chances that a different antidepressant will be effective replacement is around 30% ( Rush et al. 2006)3.-Difficulty in averaging the effect of Placebo's vs. allowing washout4.-Antidepressants are more effective at stopping relapses then placebo.

2. Neuroscientific

2.1 Depression Background

Depression is a word we often use to describe someone with sadness or a low mood. Depression is very common, on average one in five people become depressed at some stage. In Australia now there are approximately one million adults and 100 000 young people who are currently dealing with depression. Depression is more than just a simple feeling of being sad as it lasts longer, is more intense, and has a major impact on the affected person’s day-to-day functioning. Depression can be experienced in many forms :
  • Major depression - when depressed mood occurs and lasts for at least two weeks. It is usually called clinical depression.
  • Psychotic depression - is a combination of depressed mood and symptoms of psychosis. Psychosis is diagnosed as the seeing or hearing of things that are not there, extreme feelings of deluded paranoia.
  • Dysthymia - Is generally a chronic low to moderate level of depression that lasts for years.
  • Mixed depression and anxiety - a combination of both depression and anxiety symptoms.
  • Bipolar- Is fluctuating form of depression that has periods of depressed and manic moods. It can also be called manic depressive illness
(Beyond Blue 2010)

2.1.1. Diagnosis:

The most widely used diagnostic publication is currently the Diagnostic and Statistical Manual of Mental Disorders 4th Ed.
on (DSM-IV) and the The diagnostic criteria are outlined below for a major depressive episode. Depression is defined in the DSM-IV as being multiple temporally unconnected individual depressive episodes:

People who are experiencing depression experience low moods that arise regularly for at least/more than two weeks. It is common to continuously feel guilty, overwhelmed, frustrated, hopeless and disappointed with ones self.
People who are depressed have a tendency to think in a pessimistic way. They generally have negative thoughts about themselves, the world, and their future. Thoughts like:
  • feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
  • diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
  • recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
When people are depressed they often don’t show feelings of enjoyment, especially towards the things they used to enjoy. Sometimes when people become depressed they rely on alcohol and other drugs to help lift their mood. Unfortunately, this often has the opposite effect.
When people are experiencing depressing they commonly show physical symptoms like:
  • A fall in energy levels
  • Interrupted sleeping patterns (sleeping too little or too much)
  • Fatigue
  • Changes in appetite
  • significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.
    A loss in sexual interest and pleasure
  • Headache and muscle pain
  • psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

It is interesting to note that the above are all either behavioural assessments or introspective reports. Secondly there is a lot of symptom overlap between depression and other conditions (for instance manic-depressive disorder would share many of the same symptoms but include manic periods). One of the main reasons for this overlap and the potential idiopathic nature of the symptoms any two sufferers may face is that there is no physiological assessment currently available. While much research has been completed into the molecular neurobiological basis of depression (Krishnan & Nestler, 2008), its epidemiology (Patten, 2007. Patten & Schopflocher, 2008) and its genetics (Levinson, 2005). A fine grained ability to assess or predict the disease is still not possible. Two reasons are given for this (Krishnan & Nestler, 2008). Firstly depression appears to involve the interplay between an individual’s genetic and physiological makeup and the environmental cues they face. Secondly current examination of the brain relies on techniques that are still quite coarse, with MRIs and PET scans only able to see gross changes in the brain. For these reasons there are still a number of hypothesises about the cause of depression not all of which are mutually exclusive.

2.1.2 What is really happening?:

Neurotransmitters are chemical messengers in the brain that allow the communication between nerve cells in the brain. The levels of Serotonin in the brain are thought to play a role in the cause of depression. There is evidence that it is not a simple case of levels of Serotonin directly causing Depression as antidepressants cause an increase in serotonin in a matter of days, whilst relief for sufferers taking the drug may take weeks to month (Krishnan & Nestler, 2008). Secondly there have been cases of patients who have extremely low levels of Serotonin production who have not suffered from depression (Leu-Semenescu et al. 2010).
Current research sees Serotonin playing an epiphenomenonal role in depression. Packets of serotonin molecules are released from the end of the presynaptic cell called the axon, into the space between the two nerve cells called the synapse (Owens & Nemeroff, 1994) .
These molecules may then be taken up by serotonin receptors of the postsynaptic nerve cell called the dendrite and then pass along their chemical message to other nerve cells surrounding them. Excess molecules are taken back up by the presynaptic cell and reprocessed.

There are a few possible things might potentially go wrong with this process and lead to a serotonin deficit (depression). For example
  1. Not enough serotonin is being produced,
  2. Non sufficient receptor sites to receive the serotonin,
  3. Serotonin is being taken back up too quickly before it can reach receptor sites within the cell
  4. Chemical precursors (molecules that the serotonin is made from) may be in short supply
  5. There could be a short supply of molecules that assist in the production of serotonin.
(Ruhe et al. 2007)

Therefore if there is a breakdown anywhere along the path, the neurotransmitter supplies may not be adequate for the needs of the individual. Inadequate supplies lead to the symptoms that we know as depression.

2.2 Treatment:

2.2.1 TCAs:


Imipramine (Tofranil) is one of the tricyclic antidepressant family (TCA). TCA's are a class of drugs that structurally resemble a three ring molecule. TCAs are used for treatment of depression as well as producing analgesic effects. Imipramine (Tofranil) is often used as an alternative for people who are resistant to different antidepressants. This type is mainly used for long term treatment of dysthymia and bipolar depression. Tricyclics act to:
  • Block pre-synaptic serotonin and Norepinephrine re-uptake transporters
  • Block postsynaptic histamine receptors
  • Block postsynaptic norepinephrine

These neurological effects lead to elevation of mood, motivation for physical activity, increase apetite, regulate sleep patterns and decrease negative thoughts and suicidal tendencies. They are also very effective in preventing relapse into more severe major depression (Julien 2008).

According to Mavissakalian & Perel (1999) results confirm that there is a very high degree of prophylactic effectiveness of imipramine treatment. The articledemonstrates that relapse is most common in those who have a combination of panic disorder and depression but if they were in stable remission prior to treatment no relapse occurred It also stated that a patient receiving imipramine maintenance was at a 92.5% lower in the hazard rate of relapse than a patient receiving a placebo?

2.2.2 SSRI:

Paxil is a member of the Selective Serotonin Reuptake Inhibitor (SSRI) family. In the brain, messages are passed along connecting nerve cells by means of a chemical synapse which is a small gap between the cells. The presynaptic cell that sends the information releases neurotransmitters into that gap. The neurotransmitters are known by receptors on the surface of the postsynaptic cell, which stimulates a signal (Julien 2008).
To encourage the recipient cell, SSRI's slow down the reuptake of serotonin. Then the serotonin stays in the synaptic gap longer than it normally would, and may repeatedly stimulate the receptors of the recipient cell. The current model of SSRI's assumes that a lower homeostatic level of serotonin is primarily responsible for depression. While this holds in cases of major depression, minor to moderate cases are not as clear cut, and may in fact be caused by excess serotonin in specific areas of the brain (Julien 2008).
Recent research suggests that serotonin is one of the hormones that are regulated by astrocytes, and controls the uptake, putting together, and resending serotonin in a way similar to neuronal axons, but do not have corresponding post-synaptic terminals.

Paxil: was FDA approved Paxil for research in 1992. In May of 1996 Paxil was approved for the treatment of panic disorder,OCD and depression. Paxil is a member of the Selective Serotonin Reuptake Inhibitor family (SSRI’s), which increases serotonin levels in the synapse by blocking serotonin reuptake into brain cells. Peselow et al. (1992) found that Paxil was statistically superior to a placebo in a double-blind study of its effectiveness.

3. Anaylsis

3.1 Target audience

This Article appeared in the New York Times one of the most prominent English language general Newspapers in the world. The Newspaper is a broadsheet which is typically aimed at educated English speakers and has a large global readership. This particular article is aimed at educated non-specialists in the field of neuro-pharmacology.

3.2 Intention of the article

The intention of this article is to discuss the ramifications of the meta-analysis and in particular the effectiveness of anti-depressants. As it is aimed at educated non-specialists, it is aimed at clarifying research and claims that frequently appear in the media in general. Given the prevalence of depression in society, the effects and usefulness of antidepressants are regular news items. However it is rare that these articles are written by either researchers in the field or even scientifically qualified journalists. This can lead to the spread of inaccurate beliefs, in this case it may potentially lead to people suffering from depression avoiding use of available anti-depressants. Friedman is aiming to clarify the boundaries of the meta-analysis by showing that despite the meta-analysis not being flawed, given its limited scope antidepressants still provide relief for a large portion of the population.

3.3 Attitude

Dr Friedman takes a critical approach when discussing past research as he tends to emphasise only the negative aspects of the studies. His perspective on antidepressants seems biased but it is justifiable; he argues that the meta-analysis is only of partial use given the narrow range of drugs studied. Friedman acknowledges the usefulness of meta-analysis, but is critical of the selection criteria used by this study. In particular he argues that placebo washout is an unnecessary restriction.

3.4 Conclusion

In conclusion Friedman’s arguments seem reasonable. Whilst it is initially surprising that the placebo effect is so powerful, given the effectiveness of purely mental treatments like Cognitive Behavioural Therapy (Butler et al. 2006) in hindsight this made more sense. There are two reasons why the placebo effect is not problematic for the efficacy of antidepressants; Firstly in all cases the effectiveness of the drug in question was significantly greater, and secondly the effectiveness lasted far longer and reduced the probability of relapse. Finally, as Friedman points out the meta-analysis only looks at a small subset of available treatments. Given the current state of understanding regarding Depression patients frequently have to trial different possible treatments, and some never find a suitable match. This however does not negate the very real effectiveness that medication provides to the large proportion who are significantly helped.

4. Search strategy (appendix)

A member of our group came across the article previously. It was provided as a suggestion amongst a range of interesting pieces of media on different neuroscientific topics. The reasoning for its selection was that it provided a refreshing approach to media; as it was a partial attack on a published piece of reanalysis. The meta-analysis seemed at a cursory glance to present some difficulties for the use of antidepressants. In particular the placebo affect seemed much stronger than anticipated. Was the effectiveness of antidepressants just the placebo affect writ large?

In the beginning stages of the group form a basic knowledge by using Wikipedia. From there we made the swift progression to review papers - Krishnan & Nestler (2008) was particularly useful. The most illuminating finding during early research was how little is understood about the underlying causes of depression, and how much co-morbidity it shares with other mental illnesses. As we moved on to specific studies of the effectiveness of the individual antidepressants it was disconcerting to see how powerful the placebo effect was and how short most studies were for.

In conclusion, the topic was more difficult than first anticipated due to the range of theories behind the causes of depression and the work load of collating information across the medications. However much was learnt by the group about the effectiveness of medication on depression.

5. References

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